CHAPTER -1 INTRODUCTION -...

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1 CHAPTER -1 INTRODUCTION Quantitative structure activity relationship (QSAR) research field has been widely developed because of its powerful ability to predict drug activity [1,2]. QSAR models generally are mathematical equations relating chemical structure to their biological activity. QSAR models have another ability which is obtaining a deeper knowledge abo ut the mechanism of biological activity. This can be helpful for finding active site of action and also finding a basic structure for drug design. A major step in constructing the QSAR models is finding appropriate molecular descriptors that represent variations in structural property of molecules quantitatively. A lots of work have been done on a major scale on different types of drug molecules for many popular diseases. In this study we have modeled quantitatively some of antihypertensive drugs .Such as the modeling of 1,4-dihydropyridine (DHP) derivatives known as calcium channel antagonists , are used for treatment of cardiovascular diseases like hypertension and angina pectoris . 1.1 Definition of Hypertension: Hypertension or high blood pressure is a condition in which the blood pressure in the arteries is chronically elevated. With every heart beat, the heart pumps blood through the arteries to the rest of the body. Blood pressure is the force of blood that is pushing up against the walls of the blood vessels. If the pressure is too high, the heart has to work harder to pump, and this could lead to organ damage and several illnesses such as heart attack, stroke, heart failure, aneurysm, or renal failure.

Transcript of CHAPTER -1 INTRODUCTION -...

Page 1: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

1

CHAPTER -1

INTRODUCTION

Quantitative structurendashactivity relationship (QSAR) research field has been widely

developed because of its powerful ability to predict drug activity [12] QSAR

models generally are mathematical equations relating chemical structure to their

biological activity QSAR models have another ability which is obtaining a deeper

knowledge about the mechanism of biological activity This can be helpful fo r

finding active site of action and also finding a basic structure for drug design A

major step in constructing the QSAR models is finding appropriate molecular

descriptors that represent variations in structural property of molecules quantitatively

A lots of work have been done on a major scale on different types of drug molecules

for many popular diseases In this study we have modeled quantitatively some of

antihypertensive drugs Such as the modeling of 14-dihydropyridine (DHP) derivatives

known as calcium channel antagonists are used for treatment of cardiovascular

diseases like hypertension and angina pectoris

11 Definition of Hypertension

Hypertension or high blood pressure is a condition in which the blood

pressure in the arteries is chronically elevated With every heart beat the heart

pumps blood through the arteries to the rest of the body Blood pressure is the

force of blood that is pushing up against the walls of the blood vessels If the

pressure is too high the heart has to work harder to pump and this could lead to

organ damage and several illnesses such as heart attack stroke heart

failure aneurysm or renal failure

2

According to Medilexicons medicaldictionary hypertension means High

blood pressure transitory or sustained elevation of systemic arterial blood

pressure to a level likely to induce cardiovascular damage or other adverse

consequences

The normal level for blood pressure is below 12080 where 120 represents

the systolic measurement (peak pressure in the arteries) and 80 represents the

diastolic measurement (minimum pressure in the arteries) Blood pressure between

12080 and 13989 is called prehypertension (to denote increased risk of

hypertension) and a blood pressure of 14090 or above is considered

hypertension

12 Types of Hypertension

Hypertension may be primary (85 to 95 of cases) or secondary

Primary hypertension Hemodynamics and physiologic components (eg plasma

volume activity of the renin angiotensin system) vary indicating that primary

hypertension is unlikely to have a single cause Even if one factor is initially responsible

multiple factors are probably involved in sustaining elevated BP (the mosaic theory) In

afferent systemic arterioles malfunction of ion pumps on sarcolemmal membranes of

smooth muscle cells may lead to chronically increased vascular tone Heredity is a

predisposing factor but the exact mechanism is unclear Environmental factors (eg

dietary Na obesity stress) seem to affect only genetically susceptible people

Secondary hypertension Causes include renal parenchymal disease (eg chronic

glomerulonephritis or pyelonephritis polycystic renal disease connective tissue

disorders obstructive uropathy) renovascular disease (see Arterial Hypertension

Renovascular Hypertension) pheochromocytoma Cushings syndrome primary

aldosteronism congenital adrenal hyperplasia hyperthyroidism myxedema and

coarctation of the aorta Excessive alcohol intake and use of oral contraceptives are

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common causes of curable hypertension Use of sympathomimetics NSAIDs

corticosteroids cocaine or licorice commonly contributes to hypertension

13 Anti-Hypertensive Drugs

Anti-Hypertensive Drugs are medicines that help lower blood pressure Anti-

Hypertensive Drugs are used to help control blood pressure in people whose blood

pressure is too high Blood pressure is a measurement of the force with which blood

moves through the bodys system of blood vessels Although everyones blood pressure

goes up and down in the course of a typical day-getting higher when they are active and

going down when they sleep Some people have blood pressure that stays high all the

time This condition is known as hypertension Hypertension is not the same as

nervous tension People who have high blood pressure are not necessarily tense high-

strung or nervous They may not even beware of their condition Being

aware of high blood pressure and doing something to control it are extremely important

however Untreated high blood pressure can lead to diseases of the heart and arteries

kidney damage or stroke and can shorten life expectancy

Treatments for high blood pressure depend on the type of hypertension Most cases of

high blood pressure are called Essential or Primary Hypertension meaning that the high

blood pressure is not caused by some other medical condition For most people with

primary hypertension it is difficult to figure out the exact cause of the problem

However such hypertension usually can be controlled by some combination of anti -

hypertensive drugs and changes in daily habits (such as diet exercise and

weight control)

14 Major Categories Of Antihypertensive Drugs

Many different types of drugs are used alone or in combination with other drugs to

treat high blood pressure The major categories are middot

4

Angiotensin-converting Enzyme Inhibitors ACE inhibitors work by preventing

a chemical in the blood angiotensin I from being converted into a substance that

increases salt and water retention in the body These drugs also make blood

vessels relax which further reduces blood pressure ACE inhibitors are used in the

treatment of high blood pressure They may be used alone or in combination with

other medicines for high blood pressure They work by preventing a chemical in

the blood Angiotensin I from being converted into a substance that increases salt

and water retention in the body Increased salt and water retention lead to high

blood pressure ACE Inhibitors also make blood vessels relax which helps lower

blood pressure and allows more oxygen-rich blood to reach the heart

Treating high blood pressure is important because the condition puts a burden on

the heart and the arteries which can lead to permanent damage over time If

untreated high blood pressure increases the risk of heart attacks heart failure

stroke or kidney failure

ACE inhibitors may also be prescribed for other conditions For example

Captopril (Capoten) is used to treat kidney problems in people who take insulin to

control diabetes It is also given to some patients after a heart attack Heart attacks

damage and weaken the heart muscle and the damage continues even after a

person recovers from the attack This medicine helps slow down further damage to

the heart ACE inhibitors also may be used to treat congestive heart failure Some

commonly used ACE inhibitors are Benazepril (Lotensin) Captopril (Capoten)

Enalapril (Vasotec) Lisinopril (Prinivil Zestril) Quinapril (Accupril) and

Ramipril (Altace)

Angiotensin II Receptor Antagonists These drugs act at a later step in the same

process that ACE inhibitors affect Like ACE inhibitors they lower blood pressure

by relaxing blood vessels middot

5

Beta blockers Beta blockers affect the bodys response to certain nerve impulses

This in turn decreases the force and rate of the hearts contractions which lowers

blood pressure The main use of Beta Blockers is to treat high blood pressure

Some also are used to relieve the type of chest pain called Angina or to prevent

heart attacks in people who already have had one heart attack These drugs may

also be prescribed for other conditions such as migraine tremors and irregular

heart beat In eye drop form they are used to treat certain kinds of glaucoma

Some common Beta Blockers are Atenolol (Tenormin) Metoprolol (Lopressor)

Nadolol (Corgard) Propranolol (Inderal) and Timolol (Blocadren)

Blood Vessel Dilators (Vasodilators) These drugs lower blood pressure by

relaxing muscles in the blood vessel walls Vasodilators are used to treat high

blood pressure (hypertension ) By widening the arteries these drugs allow blood

to flow through more easily reducing blood pressure Controlling high blood

pressure is important because the condition puts a burden on the heart and the

arteries which can lead to permanent damage over time If untreated high blood

pressure increases the risk of heart attacks heart failure stroke or kidney failure

Vasodilators usually are prescribed with other types of blood pressure drugs and

rarely are used alone Examples of Vasodilators are Hydralazine (Apresoline) and

Minoxidil (Loniten)

Calcium Channel Blockers Drugs in this group slow the movement of calcium

into the cells of blood vessels This relaxes the blood vessels and lowers blood

pressure Calcium Channel Blockers are used to treat high blood pressure to

correct abnormal heart rhythms and to relieve the type of chest pain called Angina

Pectoris Physicians may prescribe some Calcium Channel Blockers to treat panic

attacks and Bipolar Disorder (manic depressive illness) and to prevent migraine

headache Some commonly used calcium channel blockers are Amlopidine

(Norvasc) Diltiazem (Cardizem) Isradipine (DynaCirc) Nifedipine (Adalat

Procardia) and Verapamil (Calan Isoptin Verelan)

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Diuretics These drugs control blood pressure by eliminating excess salt and

water from the body Diuretics are used to treat the build-up of excess fluid in the

body that occurs with some medical conditions such as congestive heart failure

liver disease and kidney disease Some Diuretics are also prescribed to treat high

blood pressure These drugs act on the kidneys to increase urine output This

reduces the amount of fluid in the bloodstream which in turn lowers blood

pressure There are several types of Diuretics also called Water Pillssuch as

Bumetanide (Bumex) Furosemide (Lasix) Hydrochlorothiazide (HydroDIURIL

Esidrix) Chlorothiazide (Diuril) and Chlorthalidone (Hygroton)

Nerve Blockers These drugs control nerve impulses along certain nerve

pathways This allows blood vessels to relax and lowers blood pressure

So by considering the various types of drugs most of the critical reviews

and Discoveries have been given by many of the researchers for the prediction of

some acute antihypertensive diseases ranging from small molecules to bio-

systems through their chemical structure properties

TPandya and coworkers [3] have identified common biophoric sites

(pharmacophore)in terms of Essential structural and physicochemical

requirements and secondary sites for binding and interacting with AT1 and AT2

receptors using APEX-3-D expert system on 16 N2-aryl triazolinone biphenyl

sulphonamides The results indicated that among several biophoric 3-D QSAR

models with three biophoric sites and two secondary sites describe the variation in

AT1 and AT2 antagonistic activities respectively

J M Saavedra at el [4] have studied increased systemic blood pressure and

response to exogenous Angiotensin II in Angiotensin II (Ang II) AT2 receptor-gene

disrupted mice and the model obtained reveals that the significant increase in AT1

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receptor expression in the absence of AT2 receptor transcription may be partially

responsible for the increased blood pressure and for the enhanced response to

exogenously administered Angiotensin II

K Song et al [5] examined Antiatherogenic effects of imidapril and involvement

of renin angiotensin system in experimental atherosclerosis induced by feeding a high-

cholesterol diet to Cynomolgus monkeys The results obtained suggests that

antiatherogenic effect of imidapril may be derived from reduction of local Ang II

production as well as its hypotensive action

C Skold and A Karlen[6] worked on the development of 3D-QSAR models for

AT1 and AT2 receptor affinity for a data set of 244 compounds and by using CoMFA for

AT1AT2 receptor selectivity based on the triazolinone and quinazolinone structural

classes The result shows that the main receptor involved in the renin-angiotensin system

are the Angiotensin type-1 (AT1) and type-2 (AT2) receptors which are both activated by

the endogenous octapeptide angiotensin II (AngII) and is of major importance in

cardiovascular and renal regulationA case-control study was performed by S Takami

and coworkers[7] in Japanese subjects to examine the genetic contribution of angiotensin

II type 1 receptor (AT1) and type 2 receptor (AT2) genes in human essential hypertension

The results suggest that gene polymorphisms of both angiotensin II receptors are not

directly involved in the increase of genetic risk for hypertension but that the AT1

receptor gene might contribute genetically to the increase of left ventricular mass

Recently cloned angiotensin II type 2 (AT2) receptor is a member of the seven

transmembrane G-protein coupled receptor superfamily with a relatively low sequence

homology with the angiotensin II type 1 (AT1) receptor subtype and counteracts the

growth action of AT1 receptor Intracellular third loops are known to be involved in

interactions with various G proteins Taken together these results support the notion that

intracellular third loop is the critical determinant for mutually antagonistic AT1 and AT2

receptors signaling pathways [8] On comparing the antihypertensive effect and

metabolic side effects of bendroflumethiazide with those of propranolol for mild to

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moderately severe essential hypertension were equal with both drugs Since the diuretics

are cheaper they should be the drug of first choice in this type of hypertension[9]

Quantitative Structure-Activity Relationship (QSAR) models were developed for

a series of N- (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycines derivatives for the

prediction of the activity of novel compounds as more potent ACE inhibitors Multiple

Linear Regression (MLR) and Partial Least Square (PLS) analyses were used to establish

the QSAR between ACE inhibitory activities and molecular descriptors[10]

Craig H Gelband et al [11] Evoked norepinephrine (NE) neuromodulation

involves AT1 receptor-mediated losartan-dependent rapid NE release inhibition of K+

channels and stimulation of Ca2+

channels AT1 receptor-mediated enhanced NE

neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an

increase in NE transporter tyrosine hydroxylase and dopamine β-hydroxylase mRNA

transcription

A series of N-[3-aryl(thiosulfono)propyl] piperazines piperidines has been

synthesized and evaluated for hypotensive activity for anaesthetized cats[12]

The discovery of angiotensin-receptor blockers by H M Siragy et al[13] have

revealed that antihypertensive agents are effective with impressive safety profile and

placebo-like tolerability Additionally these compounds provide benefits beyond the

reduction in blood pressure in conditions such as heart failure and in patients with type 2

diabetes and renal insufficiency

A series of 4-(diarylmethyl)-1-[3-(aryloxy) propyl] piperidines and structurally

related compounds were synthesized as calcium channel blockers and antihypertensive

agents by shanklin et al [14] The most potent compounds were those with fluoro

substituents in the 3- andor 4- positions of both rings of the diphenyl methane group

VNand and SA Doggrell[15] have reported the effects of tetraethylammonium4-

aminopyridine and bretylium on cardiovascular tissues from normal and hypertensive

rats

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Reninndashangiotensin system is used in diabetic retinopathy and as a treatment

strategy for vision-threatening disease by inducing a variety of tissue responses including

vasoconstriction inflammation oxidative stress cell hypertrophy and proliferation

angiogenesis and fibrosis[16]Renin-angiotensin and adrenergic nervous systems also

exhibit multiple levels of cross-regulation in heart failure These systems are

bidirectionally activated in concert ie activation of one system activates the other The

comparison of behavior of angiotensin II AT1 and AT2 receptors with β1-and β2-

adrenergic receptors suggest that the AT1 and β1 receptors are respectively exposed to

increased concentrations of mutually activatedinduced norepinephrine and Ang-II in the

failing human heart[17]

Kishor S Jain et al [18] have studied many advantages and uses of Selective α1-

adrenoreceptor antagonists in the arterial hypertension Multiple α1-adr subtypes holds

great promise for the discovery and development of more specific and selective drug

molecules targeting only one α1-adr subtype at a time and thus relative freedom from

side effects QSAR study on Imidazoline-1 receptor and α2-adrenergic receptor binding

affinities on human platelets using multilinear regression method indicates that an

increase in distribution coefficient and molar refractivity value together with a decrease

in average N-charge in the heterocyclic moiety of the ligands causes better binding

affinity for active site of the I1 receptors[19]

A new series of 3-benzyl-2-substituted-3H-[124]triazolo[51-b]quinazolin-9-ones

have been synthesized and reported for antihypertensive activity in vivo by

VAlagarsamy and S Pathak[20]

The electrocardiographic antiarrhythmic vasorelaxing and antihypertensive

activity as well as for in-vitro nitric oxide (NO) releasing ability for eight derivatives of

general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-

3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate shows that the

10

compounds with different pharmacophores at different locations have different mode of

action potent as antiarrhythmic and antihypertensive agents[21]

T Mavromoustakos et al [22] have studied the binding affinity for biological

evaluation of novel non-peptide antihypertensive analogues in vivo In MMK molecules

which fall in the same class of MM1 had a significant antihypertensive (40ndash80

compared to the drug losartan) activity in vivo However in vitro affinity studies showed

that losartan has considerably higher affinity

Quantitative structurendashactivity relationship (QSAR) analysis applied to a series of

nifedipine analogues containing the nitroimidazolyl group at the C-4 position and

different ester substituents at C-3 and C-5 positions of the 14-dihydropyridine (DHP)

ring Modeling of the calcium channel antagonist activity of these compounds were

established by multiple linear regression (MLR) and partial least squares (PLS)

regression A comparison of the two regression methods used showed that PLS has a

better prediction ability than MLR [23] A new series of dihydropyridine derivatives

bearing guaiacoxy- or phenoxy- propanolamine moiety on phenyl ring at 4-position of the

dihydropyridine base are associated with calcium channel and adrenoceptor antagonistic

activities[24]

S B Etcheverry et al[25 ] described that Losartan the potassium salt of 2-n-

butyl-4-chloro-5-hydroxymethyl-1-[(2rsquo-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]imidazol

is an efficient antihypertensive drug

Li-Wen Wang et al [26] synthesized a series of xanthones and xanthon

oxypropanolamines and screened for their antihypertensive and vasorelaxing activities

The vasodilating properties of xanthone derivative is due to its calcium channel and beta

adrenergic blocking effectsAnother series of potent antihypertensive 1-benzazepin-2-

one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem reveals

that desmethoxyverapamil shows the pharmacology of both phenylalkylamine (PA) and

benzothiazepinone (DTZ) calcium channel blockers[27] A series of 5-alkylsulfamoyl

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

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CellCardiology1988 20( 12) 1141-1150

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Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

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Dureng Euro J Med Chem1990 25( 4)361-368

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53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

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386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

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56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

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57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

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Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

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62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
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  • au10
  • bfnfn2
  • bcor1
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  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
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Page 2: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

2

According to Medilexicons medicaldictionary hypertension means High

blood pressure transitory or sustained elevation of systemic arterial blood

pressure to a level likely to induce cardiovascular damage or other adverse

consequences

The normal level for blood pressure is below 12080 where 120 represents

the systolic measurement (peak pressure in the arteries) and 80 represents the

diastolic measurement (minimum pressure in the arteries) Blood pressure between

12080 and 13989 is called prehypertension (to denote increased risk of

hypertension) and a blood pressure of 14090 or above is considered

hypertension

12 Types of Hypertension

Hypertension may be primary (85 to 95 of cases) or secondary

Primary hypertension Hemodynamics and physiologic components (eg plasma

volume activity of the renin angiotensin system) vary indicating that primary

hypertension is unlikely to have a single cause Even if one factor is initially responsible

multiple factors are probably involved in sustaining elevated BP (the mosaic theory) In

afferent systemic arterioles malfunction of ion pumps on sarcolemmal membranes of

smooth muscle cells may lead to chronically increased vascular tone Heredity is a

predisposing factor but the exact mechanism is unclear Environmental factors (eg

dietary Na obesity stress) seem to affect only genetically susceptible people

Secondary hypertension Causes include renal parenchymal disease (eg chronic

glomerulonephritis or pyelonephritis polycystic renal disease connective tissue

disorders obstructive uropathy) renovascular disease (see Arterial Hypertension

Renovascular Hypertension) pheochromocytoma Cushings syndrome primary

aldosteronism congenital adrenal hyperplasia hyperthyroidism myxedema and

coarctation of the aorta Excessive alcohol intake and use of oral contraceptives are

3

common causes of curable hypertension Use of sympathomimetics NSAIDs

corticosteroids cocaine or licorice commonly contributes to hypertension

13 Anti-Hypertensive Drugs

Anti-Hypertensive Drugs are medicines that help lower blood pressure Anti-

Hypertensive Drugs are used to help control blood pressure in people whose blood

pressure is too high Blood pressure is a measurement of the force with which blood

moves through the bodys system of blood vessels Although everyones blood pressure

goes up and down in the course of a typical day-getting higher when they are active and

going down when they sleep Some people have blood pressure that stays high all the

time This condition is known as hypertension Hypertension is not the same as

nervous tension People who have high blood pressure are not necessarily tense high-

strung or nervous They may not even beware of their condition Being

aware of high blood pressure and doing something to control it are extremely important

however Untreated high blood pressure can lead to diseases of the heart and arteries

kidney damage or stroke and can shorten life expectancy

Treatments for high blood pressure depend on the type of hypertension Most cases of

high blood pressure are called Essential or Primary Hypertension meaning that the high

blood pressure is not caused by some other medical condition For most people with

primary hypertension it is difficult to figure out the exact cause of the problem

However such hypertension usually can be controlled by some combination of anti -

hypertensive drugs and changes in daily habits (such as diet exercise and

weight control)

14 Major Categories Of Antihypertensive Drugs

Many different types of drugs are used alone or in combination with other drugs to

treat high blood pressure The major categories are middot

4

Angiotensin-converting Enzyme Inhibitors ACE inhibitors work by preventing

a chemical in the blood angiotensin I from being converted into a substance that

increases salt and water retention in the body These drugs also make blood

vessels relax which further reduces blood pressure ACE inhibitors are used in the

treatment of high blood pressure They may be used alone or in combination with

other medicines for high blood pressure They work by preventing a chemical in

the blood Angiotensin I from being converted into a substance that increases salt

and water retention in the body Increased salt and water retention lead to high

blood pressure ACE Inhibitors also make blood vessels relax which helps lower

blood pressure and allows more oxygen-rich blood to reach the heart

Treating high blood pressure is important because the condition puts a burden on

the heart and the arteries which can lead to permanent damage over time If

untreated high blood pressure increases the risk of heart attacks heart failure

stroke or kidney failure

ACE inhibitors may also be prescribed for other conditions For example

Captopril (Capoten) is used to treat kidney problems in people who take insulin to

control diabetes It is also given to some patients after a heart attack Heart attacks

damage and weaken the heart muscle and the damage continues even after a

person recovers from the attack This medicine helps slow down further damage to

the heart ACE inhibitors also may be used to treat congestive heart failure Some

commonly used ACE inhibitors are Benazepril (Lotensin) Captopril (Capoten)

Enalapril (Vasotec) Lisinopril (Prinivil Zestril) Quinapril (Accupril) and

Ramipril (Altace)

Angiotensin II Receptor Antagonists These drugs act at a later step in the same

process that ACE inhibitors affect Like ACE inhibitors they lower blood pressure

by relaxing blood vessels middot

5

Beta blockers Beta blockers affect the bodys response to certain nerve impulses

This in turn decreases the force and rate of the hearts contractions which lowers

blood pressure The main use of Beta Blockers is to treat high blood pressure

Some also are used to relieve the type of chest pain called Angina or to prevent

heart attacks in people who already have had one heart attack These drugs may

also be prescribed for other conditions such as migraine tremors and irregular

heart beat In eye drop form they are used to treat certain kinds of glaucoma

Some common Beta Blockers are Atenolol (Tenormin) Metoprolol (Lopressor)

Nadolol (Corgard) Propranolol (Inderal) and Timolol (Blocadren)

Blood Vessel Dilators (Vasodilators) These drugs lower blood pressure by

relaxing muscles in the blood vessel walls Vasodilators are used to treat high

blood pressure (hypertension ) By widening the arteries these drugs allow blood

to flow through more easily reducing blood pressure Controlling high blood

pressure is important because the condition puts a burden on the heart and the

arteries which can lead to permanent damage over time If untreated high blood

pressure increases the risk of heart attacks heart failure stroke or kidney failure

Vasodilators usually are prescribed with other types of blood pressure drugs and

rarely are used alone Examples of Vasodilators are Hydralazine (Apresoline) and

Minoxidil (Loniten)

Calcium Channel Blockers Drugs in this group slow the movement of calcium

into the cells of blood vessels This relaxes the blood vessels and lowers blood

pressure Calcium Channel Blockers are used to treat high blood pressure to

correct abnormal heart rhythms and to relieve the type of chest pain called Angina

Pectoris Physicians may prescribe some Calcium Channel Blockers to treat panic

attacks and Bipolar Disorder (manic depressive illness) and to prevent migraine

headache Some commonly used calcium channel blockers are Amlopidine

(Norvasc) Diltiazem (Cardizem) Isradipine (DynaCirc) Nifedipine (Adalat

Procardia) and Verapamil (Calan Isoptin Verelan)

6

Diuretics These drugs control blood pressure by eliminating excess salt and

water from the body Diuretics are used to treat the build-up of excess fluid in the

body that occurs with some medical conditions such as congestive heart failure

liver disease and kidney disease Some Diuretics are also prescribed to treat high

blood pressure These drugs act on the kidneys to increase urine output This

reduces the amount of fluid in the bloodstream which in turn lowers blood

pressure There are several types of Diuretics also called Water Pillssuch as

Bumetanide (Bumex) Furosemide (Lasix) Hydrochlorothiazide (HydroDIURIL

Esidrix) Chlorothiazide (Diuril) and Chlorthalidone (Hygroton)

Nerve Blockers These drugs control nerve impulses along certain nerve

pathways This allows blood vessels to relax and lowers blood pressure

So by considering the various types of drugs most of the critical reviews

and Discoveries have been given by many of the researchers for the prediction of

some acute antihypertensive diseases ranging from small molecules to bio-

systems through their chemical structure properties

TPandya and coworkers [3] have identified common biophoric sites

(pharmacophore)in terms of Essential structural and physicochemical

requirements and secondary sites for binding and interacting with AT1 and AT2

receptors using APEX-3-D expert system on 16 N2-aryl triazolinone biphenyl

sulphonamides The results indicated that among several biophoric 3-D QSAR

models with three biophoric sites and two secondary sites describe the variation in

AT1 and AT2 antagonistic activities respectively

J M Saavedra at el [4] have studied increased systemic blood pressure and

response to exogenous Angiotensin II in Angiotensin II (Ang II) AT2 receptor-gene

disrupted mice and the model obtained reveals that the significant increase in AT1

7

receptor expression in the absence of AT2 receptor transcription may be partially

responsible for the increased blood pressure and for the enhanced response to

exogenously administered Angiotensin II

K Song et al [5] examined Antiatherogenic effects of imidapril and involvement

of renin angiotensin system in experimental atherosclerosis induced by feeding a high-

cholesterol diet to Cynomolgus monkeys The results obtained suggests that

antiatherogenic effect of imidapril may be derived from reduction of local Ang II

production as well as its hypotensive action

C Skold and A Karlen[6] worked on the development of 3D-QSAR models for

AT1 and AT2 receptor affinity for a data set of 244 compounds and by using CoMFA for

AT1AT2 receptor selectivity based on the triazolinone and quinazolinone structural

classes The result shows that the main receptor involved in the renin-angiotensin system

are the Angiotensin type-1 (AT1) and type-2 (AT2) receptors which are both activated by

the endogenous octapeptide angiotensin II (AngII) and is of major importance in

cardiovascular and renal regulationA case-control study was performed by S Takami

and coworkers[7] in Japanese subjects to examine the genetic contribution of angiotensin

II type 1 receptor (AT1) and type 2 receptor (AT2) genes in human essential hypertension

The results suggest that gene polymorphisms of both angiotensin II receptors are not

directly involved in the increase of genetic risk for hypertension but that the AT1

receptor gene might contribute genetically to the increase of left ventricular mass

Recently cloned angiotensin II type 2 (AT2) receptor is a member of the seven

transmembrane G-protein coupled receptor superfamily with a relatively low sequence

homology with the angiotensin II type 1 (AT1) receptor subtype and counteracts the

growth action of AT1 receptor Intracellular third loops are known to be involved in

interactions with various G proteins Taken together these results support the notion that

intracellular third loop is the critical determinant for mutually antagonistic AT1 and AT2

receptors signaling pathways [8] On comparing the antihypertensive effect and

metabolic side effects of bendroflumethiazide with those of propranolol for mild to

8

moderately severe essential hypertension were equal with both drugs Since the diuretics

are cheaper they should be the drug of first choice in this type of hypertension[9]

Quantitative Structure-Activity Relationship (QSAR) models were developed for

a series of N- (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycines derivatives for the

prediction of the activity of novel compounds as more potent ACE inhibitors Multiple

Linear Regression (MLR) and Partial Least Square (PLS) analyses were used to establish

the QSAR between ACE inhibitory activities and molecular descriptors[10]

Craig H Gelband et al [11] Evoked norepinephrine (NE) neuromodulation

involves AT1 receptor-mediated losartan-dependent rapid NE release inhibition of K+

channels and stimulation of Ca2+

channels AT1 receptor-mediated enhanced NE

neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an

increase in NE transporter tyrosine hydroxylase and dopamine β-hydroxylase mRNA

transcription

A series of N-[3-aryl(thiosulfono)propyl] piperazines piperidines has been

synthesized and evaluated for hypotensive activity for anaesthetized cats[12]

The discovery of angiotensin-receptor blockers by H M Siragy et al[13] have

revealed that antihypertensive agents are effective with impressive safety profile and

placebo-like tolerability Additionally these compounds provide benefits beyond the

reduction in blood pressure in conditions such as heart failure and in patients with type 2

diabetes and renal insufficiency

A series of 4-(diarylmethyl)-1-[3-(aryloxy) propyl] piperidines and structurally

related compounds were synthesized as calcium channel blockers and antihypertensive

agents by shanklin et al [14] The most potent compounds were those with fluoro

substituents in the 3- andor 4- positions of both rings of the diphenyl methane group

VNand and SA Doggrell[15] have reported the effects of tetraethylammonium4-

aminopyridine and bretylium on cardiovascular tissues from normal and hypertensive

rats

9

Reninndashangiotensin system is used in diabetic retinopathy and as a treatment

strategy for vision-threatening disease by inducing a variety of tissue responses including

vasoconstriction inflammation oxidative stress cell hypertrophy and proliferation

angiogenesis and fibrosis[16]Renin-angiotensin and adrenergic nervous systems also

exhibit multiple levels of cross-regulation in heart failure These systems are

bidirectionally activated in concert ie activation of one system activates the other The

comparison of behavior of angiotensin II AT1 and AT2 receptors with β1-and β2-

adrenergic receptors suggest that the AT1 and β1 receptors are respectively exposed to

increased concentrations of mutually activatedinduced norepinephrine and Ang-II in the

failing human heart[17]

Kishor S Jain et al [18] have studied many advantages and uses of Selective α1-

adrenoreceptor antagonists in the arterial hypertension Multiple α1-adr subtypes holds

great promise for the discovery and development of more specific and selective drug

molecules targeting only one α1-adr subtype at a time and thus relative freedom from

side effects QSAR study on Imidazoline-1 receptor and α2-adrenergic receptor binding

affinities on human platelets using multilinear regression method indicates that an

increase in distribution coefficient and molar refractivity value together with a decrease

in average N-charge in the heterocyclic moiety of the ligands causes better binding

affinity for active site of the I1 receptors[19]

A new series of 3-benzyl-2-substituted-3H-[124]triazolo[51-b]quinazolin-9-ones

have been synthesized and reported for antihypertensive activity in vivo by

VAlagarsamy and S Pathak[20]

The electrocardiographic antiarrhythmic vasorelaxing and antihypertensive

activity as well as for in-vitro nitric oxide (NO) releasing ability for eight derivatives of

general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-

3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate shows that the

10

compounds with different pharmacophores at different locations have different mode of

action potent as antiarrhythmic and antihypertensive agents[21]

T Mavromoustakos et al [22] have studied the binding affinity for biological

evaluation of novel non-peptide antihypertensive analogues in vivo In MMK molecules

which fall in the same class of MM1 had a significant antihypertensive (40ndash80

compared to the drug losartan) activity in vivo However in vitro affinity studies showed

that losartan has considerably higher affinity

Quantitative structurendashactivity relationship (QSAR) analysis applied to a series of

nifedipine analogues containing the nitroimidazolyl group at the C-4 position and

different ester substituents at C-3 and C-5 positions of the 14-dihydropyridine (DHP)

ring Modeling of the calcium channel antagonist activity of these compounds were

established by multiple linear regression (MLR) and partial least squares (PLS)

regression A comparison of the two regression methods used showed that PLS has a

better prediction ability than MLR [23] A new series of dihydropyridine derivatives

bearing guaiacoxy- or phenoxy- propanolamine moiety on phenyl ring at 4-position of the

dihydropyridine base are associated with calcium channel and adrenoceptor antagonistic

activities[24]

S B Etcheverry et al[25 ] described that Losartan the potassium salt of 2-n-

butyl-4-chloro-5-hydroxymethyl-1-[(2rsquo-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]imidazol

is an efficient antihypertensive drug

Li-Wen Wang et al [26] synthesized a series of xanthones and xanthon

oxypropanolamines and screened for their antihypertensive and vasorelaxing activities

The vasodilating properties of xanthone derivative is due to its calcium channel and beta

adrenergic blocking effectsAnother series of potent antihypertensive 1-benzazepin-2-

one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem reveals

that desmethoxyverapamil shows the pharmacology of both phenylalkylamine (PA) and

benzothiazepinone (DTZ) calcium channel blockers[27] A series of 5-alkylsulfamoyl

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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and J L Miller Med Chem 2000 43 (14) 2770ndash2774

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BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

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Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

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84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

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and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

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88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 3: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

3

common causes of curable hypertension Use of sympathomimetics NSAIDs

corticosteroids cocaine or licorice commonly contributes to hypertension

13 Anti-Hypertensive Drugs

Anti-Hypertensive Drugs are medicines that help lower blood pressure Anti-

Hypertensive Drugs are used to help control blood pressure in people whose blood

pressure is too high Blood pressure is a measurement of the force with which blood

moves through the bodys system of blood vessels Although everyones blood pressure

goes up and down in the course of a typical day-getting higher when they are active and

going down when they sleep Some people have blood pressure that stays high all the

time This condition is known as hypertension Hypertension is not the same as

nervous tension People who have high blood pressure are not necessarily tense high-

strung or nervous They may not even beware of their condition Being

aware of high blood pressure and doing something to control it are extremely important

however Untreated high blood pressure can lead to diseases of the heart and arteries

kidney damage or stroke and can shorten life expectancy

Treatments for high blood pressure depend on the type of hypertension Most cases of

high blood pressure are called Essential or Primary Hypertension meaning that the high

blood pressure is not caused by some other medical condition For most people with

primary hypertension it is difficult to figure out the exact cause of the problem

However such hypertension usually can be controlled by some combination of anti -

hypertensive drugs and changes in daily habits (such as diet exercise and

weight control)

14 Major Categories Of Antihypertensive Drugs

Many different types of drugs are used alone or in combination with other drugs to

treat high blood pressure The major categories are middot

4

Angiotensin-converting Enzyme Inhibitors ACE inhibitors work by preventing

a chemical in the blood angiotensin I from being converted into a substance that

increases salt and water retention in the body These drugs also make blood

vessels relax which further reduces blood pressure ACE inhibitors are used in the

treatment of high blood pressure They may be used alone or in combination with

other medicines for high blood pressure They work by preventing a chemical in

the blood Angiotensin I from being converted into a substance that increases salt

and water retention in the body Increased salt and water retention lead to high

blood pressure ACE Inhibitors also make blood vessels relax which helps lower

blood pressure and allows more oxygen-rich blood to reach the heart

Treating high blood pressure is important because the condition puts a burden on

the heart and the arteries which can lead to permanent damage over time If

untreated high blood pressure increases the risk of heart attacks heart failure

stroke or kidney failure

ACE inhibitors may also be prescribed for other conditions For example

Captopril (Capoten) is used to treat kidney problems in people who take insulin to

control diabetes It is also given to some patients after a heart attack Heart attacks

damage and weaken the heart muscle and the damage continues even after a

person recovers from the attack This medicine helps slow down further damage to

the heart ACE inhibitors also may be used to treat congestive heart failure Some

commonly used ACE inhibitors are Benazepril (Lotensin) Captopril (Capoten)

Enalapril (Vasotec) Lisinopril (Prinivil Zestril) Quinapril (Accupril) and

Ramipril (Altace)

Angiotensin II Receptor Antagonists These drugs act at a later step in the same

process that ACE inhibitors affect Like ACE inhibitors they lower blood pressure

by relaxing blood vessels middot

5

Beta blockers Beta blockers affect the bodys response to certain nerve impulses

This in turn decreases the force and rate of the hearts contractions which lowers

blood pressure The main use of Beta Blockers is to treat high blood pressure

Some also are used to relieve the type of chest pain called Angina or to prevent

heart attacks in people who already have had one heart attack These drugs may

also be prescribed for other conditions such as migraine tremors and irregular

heart beat In eye drop form they are used to treat certain kinds of glaucoma

Some common Beta Blockers are Atenolol (Tenormin) Metoprolol (Lopressor)

Nadolol (Corgard) Propranolol (Inderal) and Timolol (Blocadren)

Blood Vessel Dilators (Vasodilators) These drugs lower blood pressure by

relaxing muscles in the blood vessel walls Vasodilators are used to treat high

blood pressure (hypertension ) By widening the arteries these drugs allow blood

to flow through more easily reducing blood pressure Controlling high blood

pressure is important because the condition puts a burden on the heart and the

arteries which can lead to permanent damage over time If untreated high blood

pressure increases the risk of heart attacks heart failure stroke or kidney failure

Vasodilators usually are prescribed with other types of blood pressure drugs and

rarely are used alone Examples of Vasodilators are Hydralazine (Apresoline) and

Minoxidil (Loniten)

Calcium Channel Blockers Drugs in this group slow the movement of calcium

into the cells of blood vessels This relaxes the blood vessels and lowers blood

pressure Calcium Channel Blockers are used to treat high blood pressure to

correct abnormal heart rhythms and to relieve the type of chest pain called Angina

Pectoris Physicians may prescribe some Calcium Channel Blockers to treat panic

attacks and Bipolar Disorder (manic depressive illness) and to prevent migraine

headache Some commonly used calcium channel blockers are Amlopidine

(Norvasc) Diltiazem (Cardizem) Isradipine (DynaCirc) Nifedipine (Adalat

Procardia) and Verapamil (Calan Isoptin Verelan)

6

Diuretics These drugs control blood pressure by eliminating excess salt and

water from the body Diuretics are used to treat the build-up of excess fluid in the

body that occurs with some medical conditions such as congestive heart failure

liver disease and kidney disease Some Diuretics are also prescribed to treat high

blood pressure These drugs act on the kidneys to increase urine output This

reduces the amount of fluid in the bloodstream which in turn lowers blood

pressure There are several types of Diuretics also called Water Pillssuch as

Bumetanide (Bumex) Furosemide (Lasix) Hydrochlorothiazide (HydroDIURIL

Esidrix) Chlorothiazide (Diuril) and Chlorthalidone (Hygroton)

Nerve Blockers These drugs control nerve impulses along certain nerve

pathways This allows blood vessels to relax and lowers blood pressure

So by considering the various types of drugs most of the critical reviews

and Discoveries have been given by many of the researchers for the prediction of

some acute antihypertensive diseases ranging from small molecules to bio-

systems through their chemical structure properties

TPandya and coworkers [3] have identified common biophoric sites

(pharmacophore)in terms of Essential structural and physicochemical

requirements and secondary sites for binding and interacting with AT1 and AT2

receptors using APEX-3-D expert system on 16 N2-aryl triazolinone biphenyl

sulphonamides The results indicated that among several biophoric 3-D QSAR

models with three biophoric sites and two secondary sites describe the variation in

AT1 and AT2 antagonistic activities respectively

J M Saavedra at el [4] have studied increased systemic blood pressure and

response to exogenous Angiotensin II in Angiotensin II (Ang II) AT2 receptor-gene

disrupted mice and the model obtained reveals that the significant increase in AT1

7

receptor expression in the absence of AT2 receptor transcription may be partially

responsible for the increased blood pressure and for the enhanced response to

exogenously administered Angiotensin II

K Song et al [5] examined Antiatherogenic effects of imidapril and involvement

of renin angiotensin system in experimental atherosclerosis induced by feeding a high-

cholesterol diet to Cynomolgus monkeys The results obtained suggests that

antiatherogenic effect of imidapril may be derived from reduction of local Ang II

production as well as its hypotensive action

C Skold and A Karlen[6] worked on the development of 3D-QSAR models for

AT1 and AT2 receptor affinity for a data set of 244 compounds and by using CoMFA for

AT1AT2 receptor selectivity based on the triazolinone and quinazolinone structural

classes The result shows that the main receptor involved in the renin-angiotensin system

are the Angiotensin type-1 (AT1) and type-2 (AT2) receptors which are both activated by

the endogenous octapeptide angiotensin II (AngII) and is of major importance in

cardiovascular and renal regulationA case-control study was performed by S Takami

and coworkers[7] in Japanese subjects to examine the genetic contribution of angiotensin

II type 1 receptor (AT1) and type 2 receptor (AT2) genes in human essential hypertension

The results suggest that gene polymorphisms of both angiotensin II receptors are not

directly involved in the increase of genetic risk for hypertension but that the AT1

receptor gene might contribute genetically to the increase of left ventricular mass

Recently cloned angiotensin II type 2 (AT2) receptor is a member of the seven

transmembrane G-protein coupled receptor superfamily with a relatively low sequence

homology with the angiotensin II type 1 (AT1) receptor subtype and counteracts the

growth action of AT1 receptor Intracellular third loops are known to be involved in

interactions with various G proteins Taken together these results support the notion that

intracellular third loop is the critical determinant for mutually antagonistic AT1 and AT2

receptors signaling pathways [8] On comparing the antihypertensive effect and

metabolic side effects of bendroflumethiazide with those of propranolol for mild to

8

moderately severe essential hypertension were equal with both drugs Since the diuretics

are cheaper they should be the drug of first choice in this type of hypertension[9]

Quantitative Structure-Activity Relationship (QSAR) models were developed for

a series of N- (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycines derivatives for the

prediction of the activity of novel compounds as more potent ACE inhibitors Multiple

Linear Regression (MLR) and Partial Least Square (PLS) analyses were used to establish

the QSAR between ACE inhibitory activities and molecular descriptors[10]

Craig H Gelband et al [11] Evoked norepinephrine (NE) neuromodulation

involves AT1 receptor-mediated losartan-dependent rapid NE release inhibition of K+

channels and stimulation of Ca2+

channels AT1 receptor-mediated enhanced NE

neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an

increase in NE transporter tyrosine hydroxylase and dopamine β-hydroxylase mRNA

transcription

A series of N-[3-aryl(thiosulfono)propyl] piperazines piperidines has been

synthesized and evaluated for hypotensive activity for anaesthetized cats[12]

The discovery of angiotensin-receptor blockers by H M Siragy et al[13] have

revealed that antihypertensive agents are effective with impressive safety profile and

placebo-like tolerability Additionally these compounds provide benefits beyond the

reduction in blood pressure in conditions such as heart failure and in patients with type 2

diabetes and renal insufficiency

A series of 4-(diarylmethyl)-1-[3-(aryloxy) propyl] piperidines and structurally

related compounds were synthesized as calcium channel blockers and antihypertensive

agents by shanklin et al [14] The most potent compounds were those with fluoro

substituents in the 3- andor 4- positions of both rings of the diphenyl methane group

VNand and SA Doggrell[15] have reported the effects of tetraethylammonium4-

aminopyridine and bretylium on cardiovascular tissues from normal and hypertensive

rats

9

Reninndashangiotensin system is used in diabetic retinopathy and as a treatment

strategy for vision-threatening disease by inducing a variety of tissue responses including

vasoconstriction inflammation oxidative stress cell hypertrophy and proliferation

angiogenesis and fibrosis[16]Renin-angiotensin and adrenergic nervous systems also

exhibit multiple levels of cross-regulation in heart failure These systems are

bidirectionally activated in concert ie activation of one system activates the other The

comparison of behavior of angiotensin II AT1 and AT2 receptors with β1-and β2-

adrenergic receptors suggest that the AT1 and β1 receptors are respectively exposed to

increased concentrations of mutually activatedinduced norepinephrine and Ang-II in the

failing human heart[17]

Kishor S Jain et al [18] have studied many advantages and uses of Selective α1-

adrenoreceptor antagonists in the arterial hypertension Multiple α1-adr subtypes holds

great promise for the discovery and development of more specific and selective drug

molecules targeting only one α1-adr subtype at a time and thus relative freedom from

side effects QSAR study on Imidazoline-1 receptor and α2-adrenergic receptor binding

affinities on human platelets using multilinear regression method indicates that an

increase in distribution coefficient and molar refractivity value together with a decrease

in average N-charge in the heterocyclic moiety of the ligands causes better binding

affinity for active site of the I1 receptors[19]

A new series of 3-benzyl-2-substituted-3H-[124]triazolo[51-b]quinazolin-9-ones

have been synthesized and reported for antihypertensive activity in vivo by

VAlagarsamy and S Pathak[20]

The electrocardiographic antiarrhythmic vasorelaxing and antihypertensive

activity as well as for in-vitro nitric oxide (NO) releasing ability for eight derivatives of

general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-

3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate shows that the

10

compounds with different pharmacophores at different locations have different mode of

action potent as antiarrhythmic and antihypertensive agents[21]

T Mavromoustakos et al [22] have studied the binding affinity for biological

evaluation of novel non-peptide antihypertensive analogues in vivo In MMK molecules

which fall in the same class of MM1 had a significant antihypertensive (40ndash80

compared to the drug losartan) activity in vivo However in vitro affinity studies showed

that losartan has considerably higher affinity

Quantitative structurendashactivity relationship (QSAR) analysis applied to a series of

nifedipine analogues containing the nitroimidazolyl group at the C-4 position and

different ester substituents at C-3 and C-5 positions of the 14-dihydropyridine (DHP)

ring Modeling of the calcium channel antagonist activity of these compounds were

established by multiple linear regression (MLR) and partial least squares (PLS)

regression A comparison of the two regression methods used showed that PLS has a

better prediction ability than MLR [23] A new series of dihydropyridine derivatives

bearing guaiacoxy- or phenoxy- propanolamine moiety on phenyl ring at 4-position of the

dihydropyridine base are associated with calcium channel and adrenoceptor antagonistic

activities[24]

S B Etcheverry et al[25 ] described that Losartan the potassium salt of 2-n-

butyl-4-chloro-5-hydroxymethyl-1-[(2rsquo-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]imidazol

is an efficient antihypertensive drug

Li-Wen Wang et al [26] synthesized a series of xanthones and xanthon

oxypropanolamines and screened for their antihypertensive and vasorelaxing activities

The vasodilating properties of xanthone derivative is due to its calcium channel and beta

adrenergic blocking effectsAnother series of potent antihypertensive 1-benzazepin-2-

one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem reveals

that desmethoxyverapamil shows the pharmacology of both phenylalkylamine (PA) and

benzothiazepinone (DTZ) calcium channel blockers[27] A series of 5-alkylsulfamoyl

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

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CellCardiology1988 20( 12) 1141-1150

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Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

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Dureng Euro J Med Chem1990 25( 4)361-368

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53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

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386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

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56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

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57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

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Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

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62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 4: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

4

Angiotensin-converting Enzyme Inhibitors ACE inhibitors work by preventing

a chemical in the blood angiotensin I from being converted into a substance that

increases salt and water retention in the body These drugs also make blood

vessels relax which further reduces blood pressure ACE inhibitors are used in the

treatment of high blood pressure They may be used alone or in combination with

other medicines for high blood pressure They work by preventing a chemical in

the blood Angiotensin I from being converted into a substance that increases salt

and water retention in the body Increased salt and water retention lead to high

blood pressure ACE Inhibitors also make blood vessels relax which helps lower

blood pressure and allows more oxygen-rich blood to reach the heart

Treating high blood pressure is important because the condition puts a burden on

the heart and the arteries which can lead to permanent damage over time If

untreated high blood pressure increases the risk of heart attacks heart failure

stroke or kidney failure

ACE inhibitors may also be prescribed for other conditions For example

Captopril (Capoten) is used to treat kidney problems in people who take insulin to

control diabetes It is also given to some patients after a heart attack Heart attacks

damage and weaken the heart muscle and the damage continues even after a

person recovers from the attack This medicine helps slow down further damage to

the heart ACE inhibitors also may be used to treat congestive heart failure Some

commonly used ACE inhibitors are Benazepril (Lotensin) Captopril (Capoten)

Enalapril (Vasotec) Lisinopril (Prinivil Zestril) Quinapril (Accupril) and

Ramipril (Altace)

Angiotensin II Receptor Antagonists These drugs act at a later step in the same

process that ACE inhibitors affect Like ACE inhibitors they lower blood pressure

by relaxing blood vessels middot

5

Beta blockers Beta blockers affect the bodys response to certain nerve impulses

This in turn decreases the force and rate of the hearts contractions which lowers

blood pressure The main use of Beta Blockers is to treat high blood pressure

Some also are used to relieve the type of chest pain called Angina or to prevent

heart attacks in people who already have had one heart attack These drugs may

also be prescribed for other conditions such as migraine tremors and irregular

heart beat In eye drop form they are used to treat certain kinds of glaucoma

Some common Beta Blockers are Atenolol (Tenormin) Metoprolol (Lopressor)

Nadolol (Corgard) Propranolol (Inderal) and Timolol (Blocadren)

Blood Vessel Dilators (Vasodilators) These drugs lower blood pressure by

relaxing muscles in the blood vessel walls Vasodilators are used to treat high

blood pressure (hypertension ) By widening the arteries these drugs allow blood

to flow through more easily reducing blood pressure Controlling high blood

pressure is important because the condition puts a burden on the heart and the

arteries which can lead to permanent damage over time If untreated high blood

pressure increases the risk of heart attacks heart failure stroke or kidney failure

Vasodilators usually are prescribed with other types of blood pressure drugs and

rarely are used alone Examples of Vasodilators are Hydralazine (Apresoline) and

Minoxidil (Loniten)

Calcium Channel Blockers Drugs in this group slow the movement of calcium

into the cells of blood vessels This relaxes the blood vessels and lowers blood

pressure Calcium Channel Blockers are used to treat high blood pressure to

correct abnormal heart rhythms and to relieve the type of chest pain called Angina

Pectoris Physicians may prescribe some Calcium Channel Blockers to treat panic

attacks and Bipolar Disorder (manic depressive illness) and to prevent migraine

headache Some commonly used calcium channel blockers are Amlopidine

(Norvasc) Diltiazem (Cardizem) Isradipine (DynaCirc) Nifedipine (Adalat

Procardia) and Verapamil (Calan Isoptin Verelan)

6

Diuretics These drugs control blood pressure by eliminating excess salt and

water from the body Diuretics are used to treat the build-up of excess fluid in the

body that occurs with some medical conditions such as congestive heart failure

liver disease and kidney disease Some Diuretics are also prescribed to treat high

blood pressure These drugs act on the kidneys to increase urine output This

reduces the amount of fluid in the bloodstream which in turn lowers blood

pressure There are several types of Diuretics also called Water Pillssuch as

Bumetanide (Bumex) Furosemide (Lasix) Hydrochlorothiazide (HydroDIURIL

Esidrix) Chlorothiazide (Diuril) and Chlorthalidone (Hygroton)

Nerve Blockers These drugs control nerve impulses along certain nerve

pathways This allows blood vessels to relax and lowers blood pressure

So by considering the various types of drugs most of the critical reviews

and Discoveries have been given by many of the researchers for the prediction of

some acute antihypertensive diseases ranging from small molecules to bio-

systems through their chemical structure properties

TPandya and coworkers [3] have identified common biophoric sites

(pharmacophore)in terms of Essential structural and physicochemical

requirements and secondary sites for binding and interacting with AT1 and AT2

receptors using APEX-3-D expert system on 16 N2-aryl triazolinone biphenyl

sulphonamides The results indicated that among several biophoric 3-D QSAR

models with three biophoric sites and two secondary sites describe the variation in

AT1 and AT2 antagonistic activities respectively

J M Saavedra at el [4] have studied increased systemic blood pressure and

response to exogenous Angiotensin II in Angiotensin II (Ang II) AT2 receptor-gene

disrupted mice and the model obtained reveals that the significant increase in AT1

7

receptor expression in the absence of AT2 receptor transcription may be partially

responsible for the increased blood pressure and for the enhanced response to

exogenously administered Angiotensin II

K Song et al [5] examined Antiatherogenic effects of imidapril and involvement

of renin angiotensin system in experimental atherosclerosis induced by feeding a high-

cholesterol diet to Cynomolgus monkeys The results obtained suggests that

antiatherogenic effect of imidapril may be derived from reduction of local Ang II

production as well as its hypotensive action

C Skold and A Karlen[6] worked on the development of 3D-QSAR models for

AT1 and AT2 receptor affinity for a data set of 244 compounds and by using CoMFA for

AT1AT2 receptor selectivity based on the triazolinone and quinazolinone structural

classes The result shows that the main receptor involved in the renin-angiotensin system

are the Angiotensin type-1 (AT1) and type-2 (AT2) receptors which are both activated by

the endogenous octapeptide angiotensin II (AngII) and is of major importance in

cardiovascular and renal regulationA case-control study was performed by S Takami

and coworkers[7] in Japanese subjects to examine the genetic contribution of angiotensin

II type 1 receptor (AT1) and type 2 receptor (AT2) genes in human essential hypertension

The results suggest that gene polymorphisms of both angiotensin II receptors are not

directly involved in the increase of genetic risk for hypertension but that the AT1

receptor gene might contribute genetically to the increase of left ventricular mass

Recently cloned angiotensin II type 2 (AT2) receptor is a member of the seven

transmembrane G-protein coupled receptor superfamily with a relatively low sequence

homology with the angiotensin II type 1 (AT1) receptor subtype and counteracts the

growth action of AT1 receptor Intracellular third loops are known to be involved in

interactions with various G proteins Taken together these results support the notion that

intracellular third loop is the critical determinant for mutually antagonistic AT1 and AT2

receptors signaling pathways [8] On comparing the antihypertensive effect and

metabolic side effects of bendroflumethiazide with those of propranolol for mild to

8

moderately severe essential hypertension were equal with both drugs Since the diuretics

are cheaper they should be the drug of first choice in this type of hypertension[9]

Quantitative Structure-Activity Relationship (QSAR) models were developed for

a series of N- (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycines derivatives for the

prediction of the activity of novel compounds as more potent ACE inhibitors Multiple

Linear Regression (MLR) and Partial Least Square (PLS) analyses were used to establish

the QSAR between ACE inhibitory activities and molecular descriptors[10]

Craig H Gelband et al [11] Evoked norepinephrine (NE) neuromodulation

involves AT1 receptor-mediated losartan-dependent rapid NE release inhibition of K+

channels and stimulation of Ca2+

channels AT1 receptor-mediated enhanced NE

neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an

increase in NE transporter tyrosine hydroxylase and dopamine β-hydroxylase mRNA

transcription

A series of N-[3-aryl(thiosulfono)propyl] piperazines piperidines has been

synthesized and evaluated for hypotensive activity for anaesthetized cats[12]

The discovery of angiotensin-receptor blockers by H M Siragy et al[13] have

revealed that antihypertensive agents are effective with impressive safety profile and

placebo-like tolerability Additionally these compounds provide benefits beyond the

reduction in blood pressure in conditions such as heart failure and in patients with type 2

diabetes and renal insufficiency

A series of 4-(diarylmethyl)-1-[3-(aryloxy) propyl] piperidines and structurally

related compounds were synthesized as calcium channel blockers and antihypertensive

agents by shanklin et al [14] The most potent compounds were those with fluoro

substituents in the 3- andor 4- positions of both rings of the diphenyl methane group

VNand and SA Doggrell[15] have reported the effects of tetraethylammonium4-

aminopyridine and bretylium on cardiovascular tissues from normal and hypertensive

rats

9

Reninndashangiotensin system is used in diabetic retinopathy and as a treatment

strategy for vision-threatening disease by inducing a variety of tissue responses including

vasoconstriction inflammation oxidative stress cell hypertrophy and proliferation

angiogenesis and fibrosis[16]Renin-angiotensin and adrenergic nervous systems also

exhibit multiple levels of cross-regulation in heart failure These systems are

bidirectionally activated in concert ie activation of one system activates the other The

comparison of behavior of angiotensin II AT1 and AT2 receptors with β1-and β2-

adrenergic receptors suggest that the AT1 and β1 receptors are respectively exposed to

increased concentrations of mutually activatedinduced norepinephrine and Ang-II in the

failing human heart[17]

Kishor S Jain et al [18] have studied many advantages and uses of Selective α1-

adrenoreceptor antagonists in the arterial hypertension Multiple α1-adr subtypes holds

great promise for the discovery and development of more specific and selective drug

molecules targeting only one α1-adr subtype at a time and thus relative freedom from

side effects QSAR study on Imidazoline-1 receptor and α2-adrenergic receptor binding

affinities on human platelets using multilinear regression method indicates that an

increase in distribution coefficient and molar refractivity value together with a decrease

in average N-charge in the heterocyclic moiety of the ligands causes better binding

affinity for active site of the I1 receptors[19]

A new series of 3-benzyl-2-substituted-3H-[124]triazolo[51-b]quinazolin-9-ones

have been synthesized and reported for antihypertensive activity in vivo by

VAlagarsamy and S Pathak[20]

The electrocardiographic antiarrhythmic vasorelaxing and antihypertensive

activity as well as for in-vitro nitric oxide (NO) releasing ability for eight derivatives of

general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-

3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate shows that the

10

compounds with different pharmacophores at different locations have different mode of

action potent as antiarrhythmic and antihypertensive agents[21]

T Mavromoustakos et al [22] have studied the binding affinity for biological

evaluation of novel non-peptide antihypertensive analogues in vivo In MMK molecules

which fall in the same class of MM1 had a significant antihypertensive (40ndash80

compared to the drug losartan) activity in vivo However in vitro affinity studies showed

that losartan has considerably higher affinity

Quantitative structurendashactivity relationship (QSAR) analysis applied to a series of

nifedipine analogues containing the nitroimidazolyl group at the C-4 position and

different ester substituents at C-3 and C-5 positions of the 14-dihydropyridine (DHP)

ring Modeling of the calcium channel antagonist activity of these compounds were

established by multiple linear regression (MLR) and partial least squares (PLS)

regression A comparison of the two regression methods used showed that PLS has a

better prediction ability than MLR [23] A new series of dihydropyridine derivatives

bearing guaiacoxy- or phenoxy- propanolamine moiety on phenyl ring at 4-position of the

dihydropyridine base are associated with calcium channel and adrenoceptor antagonistic

activities[24]

S B Etcheverry et al[25 ] described that Losartan the potassium salt of 2-n-

butyl-4-chloro-5-hydroxymethyl-1-[(2rsquo-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]imidazol

is an efficient antihypertensive drug

Li-Wen Wang et al [26] synthesized a series of xanthones and xanthon

oxypropanolamines and screened for their antihypertensive and vasorelaxing activities

The vasodilating properties of xanthone derivative is due to its calcium channel and beta

adrenergic blocking effectsAnother series of potent antihypertensive 1-benzazepin-2-

one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem reveals

that desmethoxyverapamil shows the pharmacology of both phenylalkylamine (PA) and

benzothiazepinone (DTZ) calcium channel blockers[27] A series of 5-alkylsulfamoyl

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

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J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

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and B Lumachi Euro J Med Chem 199025(9) 749-756

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CellCardiology1988 20( 12) 1141-1150

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Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

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Dureng Euro J Med Chem1990 25( 4)361-368

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57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

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60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

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Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

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Euro J Med Chem 1992 27(5) 527-535

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Biostructures 2009 4(2) 373 ndash 382

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and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

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71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

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74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

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and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

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82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

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Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

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88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

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94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 5: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

5

Beta blockers Beta blockers affect the bodys response to certain nerve impulses

This in turn decreases the force and rate of the hearts contractions which lowers

blood pressure The main use of Beta Blockers is to treat high blood pressure

Some also are used to relieve the type of chest pain called Angina or to prevent

heart attacks in people who already have had one heart attack These drugs may

also be prescribed for other conditions such as migraine tremors and irregular

heart beat In eye drop form they are used to treat certain kinds of glaucoma

Some common Beta Blockers are Atenolol (Tenormin) Metoprolol (Lopressor)

Nadolol (Corgard) Propranolol (Inderal) and Timolol (Blocadren)

Blood Vessel Dilators (Vasodilators) These drugs lower blood pressure by

relaxing muscles in the blood vessel walls Vasodilators are used to treat high

blood pressure (hypertension ) By widening the arteries these drugs allow blood

to flow through more easily reducing blood pressure Controlling high blood

pressure is important because the condition puts a burden on the heart and the

arteries which can lead to permanent damage over time If untreated high blood

pressure increases the risk of heart attacks heart failure stroke or kidney failure

Vasodilators usually are prescribed with other types of blood pressure drugs and

rarely are used alone Examples of Vasodilators are Hydralazine (Apresoline) and

Minoxidil (Loniten)

Calcium Channel Blockers Drugs in this group slow the movement of calcium

into the cells of blood vessels This relaxes the blood vessels and lowers blood

pressure Calcium Channel Blockers are used to treat high blood pressure to

correct abnormal heart rhythms and to relieve the type of chest pain called Angina

Pectoris Physicians may prescribe some Calcium Channel Blockers to treat panic

attacks and Bipolar Disorder (manic depressive illness) and to prevent migraine

headache Some commonly used calcium channel blockers are Amlopidine

(Norvasc) Diltiazem (Cardizem) Isradipine (DynaCirc) Nifedipine (Adalat

Procardia) and Verapamil (Calan Isoptin Verelan)

6

Diuretics These drugs control blood pressure by eliminating excess salt and

water from the body Diuretics are used to treat the build-up of excess fluid in the

body that occurs with some medical conditions such as congestive heart failure

liver disease and kidney disease Some Diuretics are also prescribed to treat high

blood pressure These drugs act on the kidneys to increase urine output This

reduces the amount of fluid in the bloodstream which in turn lowers blood

pressure There are several types of Diuretics also called Water Pillssuch as

Bumetanide (Bumex) Furosemide (Lasix) Hydrochlorothiazide (HydroDIURIL

Esidrix) Chlorothiazide (Diuril) and Chlorthalidone (Hygroton)

Nerve Blockers These drugs control nerve impulses along certain nerve

pathways This allows blood vessels to relax and lowers blood pressure

So by considering the various types of drugs most of the critical reviews

and Discoveries have been given by many of the researchers for the prediction of

some acute antihypertensive diseases ranging from small molecules to bio-

systems through their chemical structure properties

TPandya and coworkers [3] have identified common biophoric sites

(pharmacophore)in terms of Essential structural and physicochemical

requirements and secondary sites for binding and interacting with AT1 and AT2

receptors using APEX-3-D expert system on 16 N2-aryl triazolinone biphenyl

sulphonamides The results indicated that among several biophoric 3-D QSAR

models with three biophoric sites and two secondary sites describe the variation in

AT1 and AT2 antagonistic activities respectively

J M Saavedra at el [4] have studied increased systemic blood pressure and

response to exogenous Angiotensin II in Angiotensin II (Ang II) AT2 receptor-gene

disrupted mice and the model obtained reveals that the significant increase in AT1

7

receptor expression in the absence of AT2 receptor transcription may be partially

responsible for the increased blood pressure and for the enhanced response to

exogenously administered Angiotensin II

K Song et al [5] examined Antiatherogenic effects of imidapril and involvement

of renin angiotensin system in experimental atherosclerosis induced by feeding a high-

cholesterol diet to Cynomolgus monkeys The results obtained suggests that

antiatherogenic effect of imidapril may be derived from reduction of local Ang II

production as well as its hypotensive action

C Skold and A Karlen[6] worked on the development of 3D-QSAR models for

AT1 and AT2 receptor affinity for a data set of 244 compounds and by using CoMFA for

AT1AT2 receptor selectivity based on the triazolinone and quinazolinone structural

classes The result shows that the main receptor involved in the renin-angiotensin system

are the Angiotensin type-1 (AT1) and type-2 (AT2) receptors which are both activated by

the endogenous octapeptide angiotensin II (AngII) and is of major importance in

cardiovascular and renal regulationA case-control study was performed by S Takami

and coworkers[7] in Japanese subjects to examine the genetic contribution of angiotensin

II type 1 receptor (AT1) and type 2 receptor (AT2) genes in human essential hypertension

The results suggest that gene polymorphisms of both angiotensin II receptors are not

directly involved in the increase of genetic risk for hypertension but that the AT1

receptor gene might contribute genetically to the increase of left ventricular mass

Recently cloned angiotensin II type 2 (AT2) receptor is a member of the seven

transmembrane G-protein coupled receptor superfamily with a relatively low sequence

homology with the angiotensin II type 1 (AT1) receptor subtype and counteracts the

growth action of AT1 receptor Intracellular third loops are known to be involved in

interactions with various G proteins Taken together these results support the notion that

intracellular third loop is the critical determinant for mutually antagonistic AT1 and AT2

receptors signaling pathways [8] On comparing the antihypertensive effect and

metabolic side effects of bendroflumethiazide with those of propranolol for mild to

8

moderately severe essential hypertension were equal with both drugs Since the diuretics

are cheaper they should be the drug of first choice in this type of hypertension[9]

Quantitative Structure-Activity Relationship (QSAR) models were developed for

a series of N- (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycines derivatives for the

prediction of the activity of novel compounds as more potent ACE inhibitors Multiple

Linear Regression (MLR) and Partial Least Square (PLS) analyses were used to establish

the QSAR between ACE inhibitory activities and molecular descriptors[10]

Craig H Gelband et al [11] Evoked norepinephrine (NE) neuromodulation

involves AT1 receptor-mediated losartan-dependent rapid NE release inhibition of K+

channels and stimulation of Ca2+

channels AT1 receptor-mediated enhanced NE

neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an

increase in NE transporter tyrosine hydroxylase and dopamine β-hydroxylase mRNA

transcription

A series of N-[3-aryl(thiosulfono)propyl] piperazines piperidines has been

synthesized and evaluated for hypotensive activity for anaesthetized cats[12]

The discovery of angiotensin-receptor blockers by H M Siragy et al[13] have

revealed that antihypertensive agents are effective with impressive safety profile and

placebo-like tolerability Additionally these compounds provide benefits beyond the

reduction in blood pressure in conditions such as heart failure and in patients with type 2

diabetes and renal insufficiency

A series of 4-(diarylmethyl)-1-[3-(aryloxy) propyl] piperidines and structurally

related compounds were synthesized as calcium channel blockers and antihypertensive

agents by shanklin et al [14] The most potent compounds were those with fluoro

substituents in the 3- andor 4- positions of both rings of the diphenyl methane group

VNand and SA Doggrell[15] have reported the effects of tetraethylammonium4-

aminopyridine and bretylium on cardiovascular tissues from normal and hypertensive

rats

9

Reninndashangiotensin system is used in diabetic retinopathy and as a treatment

strategy for vision-threatening disease by inducing a variety of tissue responses including

vasoconstriction inflammation oxidative stress cell hypertrophy and proliferation

angiogenesis and fibrosis[16]Renin-angiotensin and adrenergic nervous systems also

exhibit multiple levels of cross-regulation in heart failure These systems are

bidirectionally activated in concert ie activation of one system activates the other The

comparison of behavior of angiotensin II AT1 and AT2 receptors with β1-and β2-

adrenergic receptors suggest that the AT1 and β1 receptors are respectively exposed to

increased concentrations of mutually activatedinduced norepinephrine and Ang-II in the

failing human heart[17]

Kishor S Jain et al [18] have studied many advantages and uses of Selective α1-

adrenoreceptor antagonists in the arterial hypertension Multiple α1-adr subtypes holds

great promise for the discovery and development of more specific and selective drug

molecules targeting only one α1-adr subtype at a time and thus relative freedom from

side effects QSAR study on Imidazoline-1 receptor and α2-adrenergic receptor binding

affinities on human platelets using multilinear regression method indicates that an

increase in distribution coefficient and molar refractivity value together with a decrease

in average N-charge in the heterocyclic moiety of the ligands causes better binding

affinity for active site of the I1 receptors[19]

A new series of 3-benzyl-2-substituted-3H-[124]triazolo[51-b]quinazolin-9-ones

have been synthesized and reported for antihypertensive activity in vivo by

VAlagarsamy and S Pathak[20]

The electrocardiographic antiarrhythmic vasorelaxing and antihypertensive

activity as well as for in-vitro nitric oxide (NO) releasing ability for eight derivatives of

general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-

3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate shows that the

10

compounds with different pharmacophores at different locations have different mode of

action potent as antiarrhythmic and antihypertensive agents[21]

T Mavromoustakos et al [22] have studied the binding affinity for biological

evaluation of novel non-peptide antihypertensive analogues in vivo In MMK molecules

which fall in the same class of MM1 had a significant antihypertensive (40ndash80

compared to the drug losartan) activity in vivo However in vitro affinity studies showed

that losartan has considerably higher affinity

Quantitative structurendashactivity relationship (QSAR) analysis applied to a series of

nifedipine analogues containing the nitroimidazolyl group at the C-4 position and

different ester substituents at C-3 and C-5 positions of the 14-dihydropyridine (DHP)

ring Modeling of the calcium channel antagonist activity of these compounds were

established by multiple linear regression (MLR) and partial least squares (PLS)

regression A comparison of the two regression methods used showed that PLS has a

better prediction ability than MLR [23] A new series of dihydropyridine derivatives

bearing guaiacoxy- or phenoxy- propanolamine moiety on phenyl ring at 4-position of the

dihydropyridine base are associated with calcium channel and adrenoceptor antagonistic

activities[24]

S B Etcheverry et al[25 ] described that Losartan the potassium salt of 2-n-

butyl-4-chloro-5-hydroxymethyl-1-[(2rsquo-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]imidazol

is an efficient antihypertensive drug

Li-Wen Wang et al [26] synthesized a series of xanthones and xanthon

oxypropanolamines and screened for their antihypertensive and vasorelaxing activities

The vasodilating properties of xanthone derivative is due to its calcium channel and beta

adrenergic blocking effectsAnother series of potent antihypertensive 1-benzazepin-2-

one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem reveals

that desmethoxyverapamil shows the pharmacology of both phenylalkylamine (PA) and

benzothiazepinone (DTZ) calcium channel blockers[27] A series of 5-alkylsulfamoyl

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

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7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

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8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

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9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

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11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

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13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

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14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 6: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

6

Diuretics These drugs control blood pressure by eliminating excess salt and

water from the body Diuretics are used to treat the build-up of excess fluid in the

body that occurs with some medical conditions such as congestive heart failure

liver disease and kidney disease Some Diuretics are also prescribed to treat high

blood pressure These drugs act on the kidneys to increase urine output This

reduces the amount of fluid in the bloodstream which in turn lowers blood

pressure There are several types of Diuretics also called Water Pillssuch as

Bumetanide (Bumex) Furosemide (Lasix) Hydrochlorothiazide (HydroDIURIL

Esidrix) Chlorothiazide (Diuril) and Chlorthalidone (Hygroton)

Nerve Blockers These drugs control nerve impulses along certain nerve

pathways This allows blood vessels to relax and lowers blood pressure

So by considering the various types of drugs most of the critical reviews

and Discoveries have been given by many of the researchers for the prediction of

some acute antihypertensive diseases ranging from small molecules to bio-

systems through their chemical structure properties

TPandya and coworkers [3] have identified common biophoric sites

(pharmacophore)in terms of Essential structural and physicochemical

requirements and secondary sites for binding and interacting with AT1 and AT2

receptors using APEX-3-D expert system on 16 N2-aryl triazolinone biphenyl

sulphonamides The results indicated that among several biophoric 3-D QSAR

models with three biophoric sites and two secondary sites describe the variation in

AT1 and AT2 antagonistic activities respectively

J M Saavedra at el [4] have studied increased systemic blood pressure and

response to exogenous Angiotensin II in Angiotensin II (Ang II) AT2 receptor-gene

disrupted mice and the model obtained reveals that the significant increase in AT1

7

receptor expression in the absence of AT2 receptor transcription may be partially

responsible for the increased blood pressure and for the enhanced response to

exogenously administered Angiotensin II

K Song et al [5] examined Antiatherogenic effects of imidapril and involvement

of renin angiotensin system in experimental atherosclerosis induced by feeding a high-

cholesterol diet to Cynomolgus monkeys The results obtained suggests that

antiatherogenic effect of imidapril may be derived from reduction of local Ang II

production as well as its hypotensive action

C Skold and A Karlen[6] worked on the development of 3D-QSAR models for

AT1 and AT2 receptor affinity for a data set of 244 compounds and by using CoMFA for

AT1AT2 receptor selectivity based on the triazolinone and quinazolinone structural

classes The result shows that the main receptor involved in the renin-angiotensin system

are the Angiotensin type-1 (AT1) and type-2 (AT2) receptors which are both activated by

the endogenous octapeptide angiotensin II (AngII) and is of major importance in

cardiovascular and renal regulationA case-control study was performed by S Takami

and coworkers[7] in Japanese subjects to examine the genetic contribution of angiotensin

II type 1 receptor (AT1) and type 2 receptor (AT2) genes in human essential hypertension

The results suggest that gene polymorphisms of both angiotensin II receptors are not

directly involved in the increase of genetic risk for hypertension but that the AT1

receptor gene might contribute genetically to the increase of left ventricular mass

Recently cloned angiotensin II type 2 (AT2) receptor is a member of the seven

transmembrane G-protein coupled receptor superfamily with a relatively low sequence

homology with the angiotensin II type 1 (AT1) receptor subtype and counteracts the

growth action of AT1 receptor Intracellular third loops are known to be involved in

interactions with various G proteins Taken together these results support the notion that

intracellular third loop is the critical determinant for mutually antagonistic AT1 and AT2

receptors signaling pathways [8] On comparing the antihypertensive effect and

metabolic side effects of bendroflumethiazide with those of propranolol for mild to

8

moderately severe essential hypertension were equal with both drugs Since the diuretics

are cheaper they should be the drug of first choice in this type of hypertension[9]

Quantitative Structure-Activity Relationship (QSAR) models were developed for

a series of N- (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycines derivatives for the

prediction of the activity of novel compounds as more potent ACE inhibitors Multiple

Linear Regression (MLR) and Partial Least Square (PLS) analyses were used to establish

the QSAR between ACE inhibitory activities and molecular descriptors[10]

Craig H Gelband et al [11] Evoked norepinephrine (NE) neuromodulation

involves AT1 receptor-mediated losartan-dependent rapid NE release inhibition of K+

channels and stimulation of Ca2+

channels AT1 receptor-mediated enhanced NE

neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an

increase in NE transporter tyrosine hydroxylase and dopamine β-hydroxylase mRNA

transcription

A series of N-[3-aryl(thiosulfono)propyl] piperazines piperidines has been

synthesized and evaluated for hypotensive activity for anaesthetized cats[12]

The discovery of angiotensin-receptor blockers by H M Siragy et al[13] have

revealed that antihypertensive agents are effective with impressive safety profile and

placebo-like tolerability Additionally these compounds provide benefits beyond the

reduction in blood pressure in conditions such as heart failure and in patients with type 2

diabetes and renal insufficiency

A series of 4-(diarylmethyl)-1-[3-(aryloxy) propyl] piperidines and structurally

related compounds were synthesized as calcium channel blockers and antihypertensive

agents by shanklin et al [14] The most potent compounds were those with fluoro

substituents in the 3- andor 4- positions of both rings of the diphenyl methane group

VNand and SA Doggrell[15] have reported the effects of tetraethylammonium4-

aminopyridine and bretylium on cardiovascular tissues from normal and hypertensive

rats

9

Reninndashangiotensin system is used in diabetic retinopathy and as a treatment

strategy for vision-threatening disease by inducing a variety of tissue responses including

vasoconstriction inflammation oxidative stress cell hypertrophy and proliferation

angiogenesis and fibrosis[16]Renin-angiotensin and adrenergic nervous systems also

exhibit multiple levels of cross-regulation in heart failure These systems are

bidirectionally activated in concert ie activation of one system activates the other The

comparison of behavior of angiotensin II AT1 and AT2 receptors with β1-and β2-

adrenergic receptors suggest that the AT1 and β1 receptors are respectively exposed to

increased concentrations of mutually activatedinduced norepinephrine and Ang-II in the

failing human heart[17]

Kishor S Jain et al [18] have studied many advantages and uses of Selective α1-

adrenoreceptor antagonists in the arterial hypertension Multiple α1-adr subtypes holds

great promise for the discovery and development of more specific and selective drug

molecules targeting only one α1-adr subtype at a time and thus relative freedom from

side effects QSAR study on Imidazoline-1 receptor and α2-adrenergic receptor binding

affinities on human platelets using multilinear regression method indicates that an

increase in distribution coefficient and molar refractivity value together with a decrease

in average N-charge in the heterocyclic moiety of the ligands causes better binding

affinity for active site of the I1 receptors[19]

A new series of 3-benzyl-2-substituted-3H-[124]triazolo[51-b]quinazolin-9-ones

have been synthesized and reported for antihypertensive activity in vivo by

VAlagarsamy and S Pathak[20]

The electrocardiographic antiarrhythmic vasorelaxing and antihypertensive

activity as well as for in-vitro nitric oxide (NO) releasing ability for eight derivatives of

general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-

3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate shows that the

10

compounds with different pharmacophores at different locations have different mode of

action potent as antiarrhythmic and antihypertensive agents[21]

T Mavromoustakos et al [22] have studied the binding affinity for biological

evaluation of novel non-peptide antihypertensive analogues in vivo In MMK molecules

which fall in the same class of MM1 had a significant antihypertensive (40ndash80

compared to the drug losartan) activity in vivo However in vitro affinity studies showed

that losartan has considerably higher affinity

Quantitative structurendashactivity relationship (QSAR) analysis applied to a series of

nifedipine analogues containing the nitroimidazolyl group at the C-4 position and

different ester substituents at C-3 and C-5 positions of the 14-dihydropyridine (DHP)

ring Modeling of the calcium channel antagonist activity of these compounds were

established by multiple linear regression (MLR) and partial least squares (PLS)

regression A comparison of the two regression methods used showed that PLS has a

better prediction ability than MLR [23] A new series of dihydropyridine derivatives

bearing guaiacoxy- or phenoxy- propanolamine moiety on phenyl ring at 4-position of the

dihydropyridine base are associated with calcium channel and adrenoceptor antagonistic

activities[24]

S B Etcheverry et al[25 ] described that Losartan the potassium salt of 2-n-

butyl-4-chloro-5-hydroxymethyl-1-[(2rsquo-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]imidazol

is an efficient antihypertensive drug

Li-Wen Wang et al [26] synthesized a series of xanthones and xanthon

oxypropanolamines and screened for their antihypertensive and vasorelaxing activities

The vasodilating properties of xanthone derivative is due to its calcium channel and beta

adrenergic blocking effectsAnother series of potent antihypertensive 1-benzazepin-2-

one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem reveals

that desmethoxyverapamil shows the pharmacology of both phenylalkylamine (PA) and

benzothiazepinone (DTZ) calcium channel blockers[27] A series of 5-alkylsulfamoyl

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

Development 2011 1 85-104

11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 7: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

7

receptor expression in the absence of AT2 receptor transcription may be partially

responsible for the increased blood pressure and for the enhanced response to

exogenously administered Angiotensin II

K Song et al [5] examined Antiatherogenic effects of imidapril and involvement

of renin angiotensin system in experimental atherosclerosis induced by feeding a high-

cholesterol diet to Cynomolgus monkeys The results obtained suggests that

antiatherogenic effect of imidapril may be derived from reduction of local Ang II

production as well as its hypotensive action

C Skold and A Karlen[6] worked on the development of 3D-QSAR models for

AT1 and AT2 receptor affinity for a data set of 244 compounds and by using CoMFA for

AT1AT2 receptor selectivity based on the triazolinone and quinazolinone structural

classes The result shows that the main receptor involved in the renin-angiotensin system

are the Angiotensin type-1 (AT1) and type-2 (AT2) receptors which are both activated by

the endogenous octapeptide angiotensin II (AngII) and is of major importance in

cardiovascular and renal regulationA case-control study was performed by S Takami

and coworkers[7] in Japanese subjects to examine the genetic contribution of angiotensin

II type 1 receptor (AT1) and type 2 receptor (AT2) genes in human essential hypertension

The results suggest that gene polymorphisms of both angiotensin II receptors are not

directly involved in the increase of genetic risk for hypertension but that the AT1

receptor gene might contribute genetically to the increase of left ventricular mass

Recently cloned angiotensin II type 2 (AT2) receptor is a member of the seven

transmembrane G-protein coupled receptor superfamily with a relatively low sequence

homology with the angiotensin II type 1 (AT1) receptor subtype and counteracts the

growth action of AT1 receptor Intracellular third loops are known to be involved in

interactions with various G proteins Taken together these results support the notion that

intracellular third loop is the critical determinant for mutually antagonistic AT1 and AT2

receptors signaling pathways [8] On comparing the antihypertensive effect and

metabolic side effects of bendroflumethiazide with those of propranolol for mild to

8

moderately severe essential hypertension were equal with both drugs Since the diuretics

are cheaper they should be the drug of first choice in this type of hypertension[9]

Quantitative Structure-Activity Relationship (QSAR) models were developed for

a series of N- (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycines derivatives for the

prediction of the activity of novel compounds as more potent ACE inhibitors Multiple

Linear Regression (MLR) and Partial Least Square (PLS) analyses were used to establish

the QSAR between ACE inhibitory activities and molecular descriptors[10]

Craig H Gelband et al [11] Evoked norepinephrine (NE) neuromodulation

involves AT1 receptor-mediated losartan-dependent rapid NE release inhibition of K+

channels and stimulation of Ca2+

channels AT1 receptor-mediated enhanced NE

neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an

increase in NE transporter tyrosine hydroxylase and dopamine β-hydroxylase mRNA

transcription

A series of N-[3-aryl(thiosulfono)propyl] piperazines piperidines has been

synthesized and evaluated for hypotensive activity for anaesthetized cats[12]

The discovery of angiotensin-receptor blockers by H M Siragy et al[13] have

revealed that antihypertensive agents are effective with impressive safety profile and

placebo-like tolerability Additionally these compounds provide benefits beyond the

reduction in blood pressure in conditions such as heart failure and in patients with type 2

diabetes and renal insufficiency

A series of 4-(diarylmethyl)-1-[3-(aryloxy) propyl] piperidines and structurally

related compounds were synthesized as calcium channel blockers and antihypertensive

agents by shanklin et al [14] The most potent compounds were those with fluoro

substituents in the 3- andor 4- positions of both rings of the diphenyl methane group

VNand and SA Doggrell[15] have reported the effects of tetraethylammonium4-

aminopyridine and bretylium on cardiovascular tissues from normal and hypertensive

rats

9

Reninndashangiotensin system is used in diabetic retinopathy and as a treatment

strategy for vision-threatening disease by inducing a variety of tissue responses including

vasoconstriction inflammation oxidative stress cell hypertrophy and proliferation

angiogenesis and fibrosis[16]Renin-angiotensin and adrenergic nervous systems also

exhibit multiple levels of cross-regulation in heart failure These systems are

bidirectionally activated in concert ie activation of one system activates the other The

comparison of behavior of angiotensin II AT1 and AT2 receptors with β1-and β2-

adrenergic receptors suggest that the AT1 and β1 receptors are respectively exposed to

increased concentrations of mutually activatedinduced norepinephrine and Ang-II in the

failing human heart[17]

Kishor S Jain et al [18] have studied many advantages and uses of Selective α1-

adrenoreceptor antagonists in the arterial hypertension Multiple α1-adr subtypes holds

great promise for the discovery and development of more specific and selective drug

molecules targeting only one α1-adr subtype at a time and thus relative freedom from

side effects QSAR study on Imidazoline-1 receptor and α2-adrenergic receptor binding

affinities on human platelets using multilinear regression method indicates that an

increase in distribution coefficient and molar refractivity value together with a decrease

in average N-charge in the heterocyclic moiety of the ligands causes better binding

affinity for active site of the I1 receptors[19]

A new series of 3-benzyl-2-substituted-3H-[124]triazolo[51-b]quinazolin-9-ones

have been synthesized and reported for antihypertensive activity in vivo by

VAlagarsamy and S Pathak[20]

The electrocardiographic antiarrhythmic vasorelaxing and antihypertensive

activity as well as for in-vitro nitric oxide (NO) releasing ability for eight derivatives of

general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-

3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate shows that the

10

compounds with different pharmacophores at different locations have different mode of

action potent as antiarrhythmic and antihypertensive agents[21]

T Mavromoustakos et al [22] have studied the binding affinity for biological

evaluation of novel non-peptide antihypertensive analogues in vivo In MMK molecules

which fall in the same class of MM1 had a significant antihypertensive (40ndash80

compared to the drug losartan) activity in vivo However in vitro affinity studies showed

that losartan has considerably higher affinity

Quantitative structurendashactivity relationship (QSAR) analysis applied to a series of

nifedipine analogues containing the nitroimidazolyl group at the C-4 position and

different ester substituents at C-3 and C-5 positions of the 14-dihydropyridine (DHP)

ring Modeling of the calcium channel antagonist activity of these compounds were

established by multiple linear regression (MLR) and partial least squares (PLS)

regression A comparison of the two regression methods used showed that PLS has a

better prediction ability than MLR [23] A new series of dihydropyridine derivatives

bearing guaiacoxy- or phenoxy- propanolamine moiety on phenyl ring at 4-position of the

dihydropyridine base are associated with calcium channel and adrenoceptor antagonistic

activities[24]

S B Etcheverry et al[25 ] described that Losartan the potassium salt of 2-n-

butyl-4-chloro-5-hydroxymethyl-1-[(2rsquo-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]imidazol

is an efficient antihypertensive drug

Li-Wen Wang et al [26] synthesized a series of xanthones and xanthon

oxypropanolamines and screened for their antihypertensive and vasorelaxing activities

The vasodilating properties of xanthone derivative is due to its calcium channel and beta

adrenergic blocking effectsAnother series of potent antihypertensive 1-benzazepin-2-

one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem reveals

that desmethoxyverapamil shows the pharmacology of both phenylalkylamine (PA) and

benzothiazepinone (DTZ) calcium channel blockers[27] A series of 5-alkylsulfamoyl

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

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22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 8: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

8

moderately severe essential hypertension were equal with both drugs Since the diuretics

are cheaper they should be the drug of first choice in this type of hypertension[9]

Quantitative Structure-Activity Relationship (QSAR) models were developed for

a series of N- (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycines derivatives for the

prediction of the activity of novel compounds as more potent ACE inhibitors Multiple

Linear Regression (MLR) and Partial Least Square (PLS) analyses were used to establish

the QSAR between ACE inhibitory activities and molecular descriptors[10]

Craig H Gelband et al [11] Evoked norepinephrine (NE) neuromodulation

involves AT1 receptor-mediated losartan-dependent rapid NE release inhibition of K+

channels and stimulation of Ca2+

channels AT1 receptor-mediated enhanced NE

neuromodulation involves the Ras-Raf-MAP kinase cascade and ultimately leads to an

increase in NE transporter tyrosine hydroxylase and dopamine β-hydroxylase mRNA

transcription

A series of N-[3-aryl(thiosulfono)propyl] piperazines piperidines has been

synthesized and evaluated for hypotensive activity for anaesthetized cats[12]

The discovery of angiotensin-receptor blockers by H M Siragy et al[13] have

revealed that antihypertensive agents are effective with impressive safety profile and

placebo-like tolerability Additionally these compounds provide benefits beyond the

reduction in blood pressure in conditions such as heart failure and in patients with type 2

diabetes and renal insufficiency

A series of 4-(diarylmethyl)-1-[3-(aryloxy) propyl] piperidines and structurally

related compounds were synthesized as calcium channel blockers and antihypertensive

agents by shanklin et al [14] The most potent compounds were those with fluoro

substituents in the 3- andor 4- positions of both rings of the diphenyl methane group

VNand and SA Doggrell[15] have reported the effects of tetraethylammonium4-

aminopyridine and bretylium on cardiovascular tissues from normal and hypertensive

rats

9

Reninndashangiotensin system is used in diabetic retinopathy and as a treatment

strategy for vision-threatening disease by inducing a variety of tissue responses including

vasoconstriction inflammation oxidative stress cell hypertrophy and proliferation

angiogenesis and fibrosis[16]Renin-angiotensin and adrenergic nervous systems also

exhibit multiple levels of cross-regulation in heart failure These systems are

bidirectionally activated in concert ie activation of one system activates the other The

comparison of behavior of angiotensin II AT1 and AT2 receptors with β1-and β2-

adrenergic receptors suggest that the AT1 and β1 receptors are respectively exposed to

increased concentrations of mutually activatedinduced norepinephrine and Ang-II in the

failing human heart[17]

Kishor S Jain et al [18] have studied many advantages and uses of Selective α1-

adrenoreceptor antagonists in the arterial hypertension Multiple α1-adr subtypes holds

great promise for the discovery and development of more specific and selective drug

molecules targeting only one α1-adr subtype at a time and thus relative freedom from

side effects QSAR study on Imidazoline-1 receptor and α2-adrenergic receptor binding

affinities on human platelets using multilinear regression method indicates that an

increase in distribution coefficient and molar refractivity value together with a decrease

in average N-charge in the heterocyclic moiety of the ligands causes better binding

affinity for active site of the I1 receptors[19]

A new series of 3-benzyl-2-substituted-3H-[124]triazolo[51-b]quinazolin-9-ones

have been synthesized and reported for antihypertensive activity in vivo by

VAlagarsamy and S Pathak[20]

The electrocardiographic antiarrhythmic vasorelaxing and antihypertensive

activity as well as for in-vitro nitric oxide (NO) releasing ability for eight derivatives of

general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-

3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate shows that the

10

compounds with different pharmacophores at different locations have different mode of

action potent as antiarrhythmic and antihypertensive agents[21]

T Mavromoustakos et al [22] have studied the binding affinity for biological

evaluation of novel non-peptide antihypertensive analogues in vivo In MMK molecules

which fall in the same class of MM1 had a significant antihypertensive (40ndash80

compared to the drug losartan) activity in vivo However in vitro affinity studies showed

that losartan has considerably higher affinity

Quantitative structurendashactivity relationship (QSAR) analysis applied to a series of

nifedipine analogues containing the nitroimidazolyl group at the C-4 position and

different ester substituents at C-3 and C-5 positions of the 14-dihydropyridine (DHP)

ring Modeling of the calcium channel antagonist activity of these compounds were

established by multiple linear regression (MLR) and partial least squares (PLS)

regression A comparison of the two regression methods used showed that PLS has a

better prediction ability than MLR [23] A new series of dihydropyridine derivatives

bearing guaiacoxy- or phenoxy- propanolamine moiety on phenyl ring at 4-position of the

dihydropyridine base are associated with calcium channel and adrenoceptor antagonistic

activities[24]

S B Etcheverry et al[25 ] described that Losartan the potassium salt of 2-n-

butyl-4-chloro-5-hydroxymethyl-1-[(2rsquo-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]imidazol

is an efficient antihypertensive drug

Li-Wen Wang et al [26] synthesized a series of xanthones and xanthon

oxypropanolamines and screened for their antihypertensive and vasorelaxing activities

The vasodilating properties of xanthone derivative is due to its calcium channel and beta

adrenergic blocking effectsAnother series of potent antihypertensive 1-benzazepin-2-

one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem reveals

that desmethoxyverapamil shows the pharmacology of both phenylalkylamine (PA) and

benzothiazepinone (DTZ) calcium channel blockers[27] A series of 5-alkylsulfamoyl

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

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63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

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Biostructures 2009 4(2) 373 ndash 382

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Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

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71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

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73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

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74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

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J Med Chem1987 22(3) 221-228

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79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

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80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 9: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

9

Reninndashangiotensin system is used in diabetic retinopathy and as a treatment

strategy for vision-threatening disease by inducing a variety of tissue responses including

vasoconstriction inflammation oxidative stress cell hypertrophy and proliferation

angiogenesis and fibrosis[16]Renin-angiotensin and adrenergic nervous systems also

exhibit multiple levels of cross-regulation in heart failure These systems are

bidirectionally activated in concert ie activation of one system activates the other The

comparison of behavior of angiotensin II AT1 and AT2 receptors with β1-and β2-

adrenergic receptors suggest that the AT1 and β1 receptors are respectively exposed to

increased concentrations of mutually activatedinduced norepinephrine and Ang-II in the

failing human heart[17]

Kishor S Jain et al [18] have studied many advantages and uses of Selective α1-

adrenoreceptor antagonists in the arterial hypertension Multiple α1-adr subtypes holds

great promise for the discovery and development of more specific and selective drug

molecules targeting only one α1-adr subtype at a time and thus relative freedom from

side effects QSAR study on Imidazoline-1 receptor and α2-adrenergic receptor binding

affinities on human platelets using multilinear regression method indicates that an

increase in distribution coefficient and molar refractivity value together with a decrease

in average N-charge in the heterocyclic moiety of the ligands causes better binding

affinity for active site of the I1 receptors[19]

A new series of 3-benzyl-2-substituted-3H-[124]triazolo[51-b]quinazolin-9-ones

have been synthesized and reported for antihypertensive activity in vivo by

VAlagarsamy and S Pathak[20]

The electrocardiographic antiarrhythmic vasorelaxing and antihypertensive

activity as well as for in-vitro nitric oxide (NO) releasing ability for eight derivatives of

general formula 2-(2-(4-(3-((5-substituted methylene)-4-oxo-2-(phenylimino)thiazolidin-

3-yl)-2-hydroxypropylamino)benzoyl)hydrazinyl)-2-oxoethyl nitrate shows that the

10

compounds with different pharmacophores at different locations have different mode of

action potent as antiarrhythmic and antihypertensive agents[21]

T Mavromoustakos et al [22] have studied the binding affinity for biological

evaluation of novel non-peptide antihypertensive analogues in vivo In MMK molecules

which fall in the same class of MM1 had a significant antihypertensive (40ndash80

compared to the drug losartan) activity in vivo However in vitro affinity studies showed

that losartan has considerably higher affinity

Quantitative structurendashactivity relationship (QSAR) analysis applied to a series of

nifedipine analogues containing the nitroimidazolyl group at the C-4 position and

different ester substituents at C-3 and C-5 positions of the 14-dihydropyridine (DHP)

ring Modeling of the calcium channel antagonist activity of these compounds were

established by multiple linear regression (MLR) and partial least squares (PLS)

regression A comparison of the two regression methods used showed that PLS has a

better prediction ability than MLR [23] A new series of dihydropyridine derivatives

bearing guaiacoxy- or phenoxy- propanolamine moiety on phenyl ring at 4-position of the

dihydropyridine base are associated with calcium channel and adrenoceptor antagonistic

activities[24]

S B Etcheverry et al[25 ] described that Losartan the potassium salt of 2-n-

butyl-4-chloro-5-hydroxymethyl-1-[(2rsquo-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]imidazol

is an efficient antihypertensive drug

Li-Wen Wang et al [26] synthesized a series of xanthones and xanthon

oxypropanolamines and screened for their antihypertensive and vasorelaxing activities

The vasodilating properties of xanthone derivative is due to its calcium channel and beta

adrenergic blocking effectsAnother series of potent antihypertensive 1-benzazepin-2-

one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem reveals

that desmethoxyverapamil shows the pharmacology of both phenylalkylamine (PA) and

benzothiazepinone (DTZ) calcium channel blockers[27] A series of 5-alkylsulfamoyl

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

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11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 10: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

10

compounds with different pharmacophores at different locations have different mode of

action potent as antiarrhythmic and antihypertensive agents[21]

T Mavromoustakos et al [22] have studied the binding affinity for biological

evaluation of novel non-peptide antihypertensive analogues in vivo In MMK molecules

which fall in the same class of MM1 had a significant antihypertensive (40ndash80

compared to the drug losartan) activity in vivo However in vitro affinity studies showed

that losartan has considerably higher affinity

Quantitative structurendashactivity relationship (QSAR) analysis applied to a series of

nifedipine analogues containing the nitroimidazolyl group at the C-4 position and

different ester substituents at C-3 and C-5 positions of the 14-dihydropyridine (DHP)

ring Modeling of the calcium channel antagonist activity of these compounds were

established by multiple linear regression (MLR) and partial least squares (PLS)

regression A comparison of the two regression methods used showed that PLS has a

better prediction ability than MLR [23] A new series of dihydropyridine derivatives

bearing guaiacoxy- or phenoxy- propanolamine moiety on phenyl ring at 4-position of the

dihydropyridine base are associated with calcium channel and adrenoceptor antagonistic

activities[24]

S B Etcheverry et al[25 ] described that Losartan the potassium salt of 2-n-

butyl-4-chloro-5-hydroxymethyl-1-[(2rsquo-(1H-tetrazol-5-yl)biphenyl-4yl)methyl]imidazol

is an efficient antihypertensive drug

Li-Wen Wang et al [26] synthesized a series of xanthones and xanthon

oxypropanolamines and screened for their antihypertensive and vasorelaxing activities

The vasodilating properties of xanthone derivative is due to its calcium channel and beta

adrenergic blocking effectsAnother series of potent antihypertensive 1-benzazepin-2-

one calcium channel blockers (CCBs) 1 that are structurally related to diltiazem reveals

that desmethoxyverapamil shows the pharmacology of both phenylalkylamine (PA) and

benzothiazepinone (DTZ) calcium channel blockers[27] A series of 5-alkylsulfamoyl

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

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Chem200210( 3) 719-730

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Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

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29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

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30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

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42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 11: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

11

benzimidazole derivatives as novel angiotensin II (Ang II) receptor antagonists have

been evaluated for in vitro Ang II antagonism and for in vivo antihypertensive activity on

isolated rat The maximum activity is observed with a compact and bulky alkyl group like

tert-butyl and cyclohexyl [28]

Biological interactions in human are currently attracting our attention particularly

in the area of QSAR (quantitative structurendashactivity relationships) In the present review

an attempt has been made to collect the data for the effect of chemicals in human and

discussed by the formulation of a total number of 37 QSAR[29]In an another approach

the 3D-QSAR analysis was carried out by PHASE program and a statistically reliable

model with good predictive power (r2thinsp=thinsp098 q

2thinsp=thinsp074) was achieved The 3D-QSAR

plots illustrated the structure-activity relationship of test compounds which may aid in the

design of potent p-hydroxybenzohydrazide derivatives as antihypertensive agents[30]

N Takaet al [31] found an ideal antihypertensive potassium channel opener

(KCO)N-(2-cyanoethyl)-22-bis(fluoromethyl)-6-pentafluoroethyl-2H-1-benzopyran-4-

carboxamide ( KC-515) showing highly potent slow and long-lasting antihypertensive

effect with reduced reflex tachycardia together with the beneficial effects of KCO such

as improvement in lipid metabolism with KC-515 as a potential candidate The

antihypertensive activity of the thieno[34-b]pyran and thieno[23-b]pyran isosteres of the

potassium channel opener (PCO) reveals that introduction of a strong electron

withdrawing group in the 2-position of the thieno[32-b] series increased potency

Similarly substitution on the thieno[34-b] series significantly lowered potency [32 ]

JT Nguyen et al[33] prepared 14-dihydropyridines containing a diazen-1-ium-

12-diolate nitric oxide donor moiety to study calcium channel antagonist structurendash

activity relationships and nitric oxide release The results from this study suggest this

class of hybrid calcium channel antagonistnitric oxide donor prodrugs should release the

vasodilator nitric oxide in vivo preferentially in the vascular endothelium to enhance the

smooth muscle calcium channel antagonist effect to produce a combined synergist ic

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

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understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

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3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

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4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

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7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

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9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

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12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

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13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

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14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 12: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

12

antihypertensive effect In another research the benzothiazepinone (diltiazem) and

benzazepinone( calcium channel blockers) serves primarily to orient two critical

pharmacophores in Space All compounds which positioned the pharmacophores on the

same face of the molecule demonstrated vasorelaxant activity[34]

W L Cody et al [35] reported the discovery and preparation of a new class of

novel cis-disubstituted amino-aryl-piperidines as a mixture of enantiomers that are potent

in vitro renin inhibitors and also possess in vivo antihypertensive activity in a double

transgenic mouse model Synthesis and screening of a chemical library of 14-

dihydropyridine calcium channel blockers from keto ester diketone and aldehyde

building blocks on a cleavable amine polymeric support have been described by MF

Gordeev et al [36]

The Comparison of isradipine and diltiazem in the treatment of essential

hypertension Ninety-five patients with mild to moderate essential hypertension revealed

that a small transient rise in heart rate for patients receiving isradipine and a significant

decrease in heart rate for patients receiving diltiazem Isradipine is generally well

tolerated by most patients and is more potent than diltiazem in lowering blood pressure

[37] T Pandya et al [38] reported 3-D QSAR studies of triazolinone based balanced

AT1AT2 receptor antagonists

The structure pKa lipophilicity solubility absorption and polar surface area of

some centrally acting antihypertensives substituted imidazoline and oxazoline structures

act as potent agonists and antagonists of imidazoline receptors[39]Recently the gene

expression programming a novel machine learning algorithm is used to develop

quantitative model as a potential screening mechanism for a series of 14-dihydropyridine

calcium channel antagonists for the first time [40] The heuristic method was used to

search nonlinear six-descriptor model responsible for activity It provides a new and

effective method for drug design and screening

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 13: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

13

The angiotensin II antagonistic activities for a series of benzimidazole derivatives

bearing a heterocyclic ring imidazole 5-chloroimidazole 124-triazol and imidazoline

groups were biologically evaluated in vitro using an AT1 receptor binding assay where

compounds imidazole and 124-triazol provided weak binding affinity compound 5-

chloroimidazole showed moderate binding affinity and compound imidazoline showed

good binding affinity Moreover imidazoline was found to be almost equipotent with

telmisartan in vivo biological evaluation study [41]In another work some 2-

nonsubstituted2-methyl-2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-45-

dihydro-3(2H)-pyridazinone derivatives and 2-nonsubstituted2-methyl- 4-[4-

(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were examined for

antihypertensive activity both in vitro and in vivo Some pyridazinone derivatives showed

appreciable activity[42]

Antihypertensive activity of hydrazidones containing Hydrazides of amino acids

and acylamino acids were condensed with 2-chlorobenzaldehyde or 2-

chloroacetophenone were evaluated In some cases the activities were similar or higher

than those of the reference compounds [43]

QSAR study on antihypertensive activity of a series of alkylN-[diphenyl

alkyl]aminoalkyl-4-aryl-14-dihydro-26-dimethyl pyridine-35 di-carboxylates was done

by Agrawal and khadikar [44] They used a large pool of topological indices along with

indicator parameters related to type of present set of compounds Another series of 6-

(Substituted-phenyl)-2-(substitutedmethyl)-45-dihydropyridazin-3(2H)-one derivatives

were synthesized by reacting 6-substitued-phenyl-45-dihydropyridazine-3(2H)-one with

different heterocyclic base under Mannich reaction conditions were evaluated for

antihypertensive activity in rats The only seven compounds showed good

antihypertensive activity[45]

A number of 2-phenoxyalkylaminoalkyl- and 2-[14] benzo dioxanyl

methylaminoalkyl-3(2H)-pyridazinones were synthesized and tested for hypotensive and

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

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3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

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4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

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7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

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8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

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9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

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12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

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13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

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14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 14: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

14

antihypertensive activity as well as for α1- and α2-adrenoceptor binding affinities Some

derivatives showed strong hypotensiveantihypertensive effect and high affinity for α 2-

and α1-adrenoceptors possessing potassium channel opening activity mode of action[46]

Another series of 44a-dihydro-5H-[1]benzopyrano[43-c]pyridazin-3-(2H)-ones have

been prepared and evaluated for their pharmacological profile as antihypertensive and

antithrombotic agents by G Cignarella et al[47]

J D Marsh et al [48] studied the effect of a dihydropyridine calcium channel

blocker with phosphodiesterase inhibitory activity ie RS93522 on cultured vascular

smooth muscle and cultured heart cells chick embryo ventricular cells Ca channel

antagonists has a negative inotropic effect on cultured myocardial cells also has

phosphodiesterase inhibitory activity that possibly may potentiate vasodil atation and

ameliorate in part negative inotropic effects Thus RS93522 has two distinct

pharmacodynamic effects in myocytes and is a potent calcium channel blocker

In recent years 4 classes of agents (diuretics β blockers converting enzyme

inhibitors and calcium channel blockers) are effective and well tolerated as single therapy

and considered as firstline drug therapy On comparing the nitrendipine (a calcium

channel blocker) and hydrochlorothiazide (a diuretic) antihypertensive activity seperately

in mild to moderate hypertension found to be equivalent in antihypertensive effects and

in frequency of adverse reactions And on combination a further decrease in blood

pressure was observed Patient characteristics affecting drug choice and clinical situations

in which calcium channel blockers can be used most effectively can now often be

delineated[49]

A series of asymmetric 4-aryl-14-dihydropyridine-35-dicarboxylates

characterized by the presence of a 33-diphenyl-propylamino moiety in one of the ester

groups were synthesized by A Leonardi et al[50] exhibiting remarkable antihypertensive

activity in spontaneously hypertensive rats as well as affinity for the 14-dihydropyridines

binding site labelled by 3H-nitrendipine in the calcium channel Introduction of this bulky

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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CG Kokotos P Kontogianni A

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Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

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Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

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36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

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J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

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41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

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43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

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45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

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48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

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925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

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59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

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60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

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62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

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82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 15: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

15

and lipophilic amine with branched propylene bridge between the ester and the amino

groups confers to the whole series an elevated level of antihypertensive activity and a

long duration of action Thus the presence of the amino group is essential for oral

activityThe concept of bioisosterism between benzoxazolinone and pyrocatechol to the

synthesis of benzoxazolinone analogues of the catecholamines were investigated for α-

and β-adrenoceptor blocking properties and for antihypertensive activity by replacing

alkylamine moiety with 1-arylpiperazines or 4-benzylpiperidine in the above reported

amino ketone and amino alcohol derivatives of benzoxazolinone[51]

New antihypertensive agents have been found with favorable hemodynamic and

metabolic profiles such as Calcium channel blockers(nitrendipine) in combination with

other antihypertensive agents( propranolol) possessing blood pressure-lowering

effectiveness Preliminary results showed that propranolol was associated with a higher

incidence of side effects However on addition of propranolol to nitrendipine

monotherapy produced a further decrease in blood pressure These data suggest that

nitrendipine provides additional effective and safe antihypertensive therapy which can be

used in place of or in combination with β blockers [52]

Another series of β-blockerdiuretic agents via oxypropanolamines and

iminoxypropanolamines containing aminic substituent 2-(4-chloro-3-

sulfamoylbenzamido)-ethyl group were synthesized and tested for β1-adrenoceptor

affinity β-blocking potency diuretic and antihypertensive properties as well as affinity

for α1-adrenoceptors by V Cecchetti [53] Only two Compounds were found to display

contemporaneously β-blocking diuretic and antihypertensive activities

Multiple linear regression (MLR) and artificial neural networks (ANN) have been

used for structurendashactivity relationship analysis for a set of 113 AT1 receptor antagonists

The ANN model showed better performance than MLR The three descriptors hydration

energy (EH) n-octanolwater partition (LOGP) and energy of the lowest unoccupied

molecular orbital (LUMO) play an important role on the activity of AT1 receptor

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 16: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

16

antagonists with biphenyl tetrazole structures This information is pertinent to the further

design of new AT1 receptor antagonists [54]

B Malawska et al[55] synthesized a series of 1-substituted pyrrolidin-2-one and

pyrrolidine derivatives and tested for electrocardiographic antiarrhythmic and

antihypertensive activity as well as for α1- and α2-adrenoceptors binding affinities The

pharmacological results and binding studies suggest that their antiarrhythmic and

hypotensive effects may be related to their α-adrenolytic properties and that these

properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or

chloro- substituent in the ortho position in the phenyl ringA another series of 4-(N-

methylencycloalkylamino)-18-naphthyridine derivatives variously substituted in

positions were synthesized and pharmacologically investigated for possible

antihypertensive activity These compounds were tested to determine a possible

vasodilator mechanism of action[56]

A number of thienocinnolin-3-(2H)-ones have been compared with the bioisoster

8-acetylamino-4 4a 5 6-tetrahydrobenzo (h)cinnolin-3-(2H)-one a potent

antihypertensive and antithrombotic agent Binding studies on phosphodiesterase (PDE)

isoenzymes indicate that earlier reported compounds displayed antihypertensive

properties while all the new derivatives exhibited lower hypotensive activity [57]

A novel series of arylpiperazines bearing a 33-diphenylpyrrolidin-2-one fragment

and evaluated for their binding affinity for α1- and α2-adrenoceptors (ARs) as well as

their antiarrhythmic and antihypertensive activities It was found that the introduction of

two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave

compounds with affinity for both α1- and α2-AR The substitution of the 2nd position in

the phenyl piperazinyl fragment of the molecule was crucial for activity[58]

A Ma Velaacutezquez [59] prepared methylthiomorpholinphenol(1) compounds from

phenol derivatives and thiomorpholine exhibiting cardiovascular activity The study was

made comparing with drugs such as captopril omapatrilat and losartan The result shows

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

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1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

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3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

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4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

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5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

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7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

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10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

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11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

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13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

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14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

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21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

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CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

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26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
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  • BM699037_ja
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Page 17: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

17

that the reported compound does not reduce blood pressure in a sudden manner as in the

case of vasodilatations and β-adrenergic blockers angiotensin-converting enzyme

inhibitors (ACE) receptors AT1 antagonists and neutral endopeptidase inhibitors The

Pharmacological testing of seven 2-substituted 3-[4-[3-(4-aryl-1-piperazinyl)-isopropano-

loxy]-phenyl]-4(3H) quinazolones showed that some of the compounds possessed

pronounced and sustained hypotensive effects as tested in anesthetized normotensive

rabbits adrenoreceptor antagonist properties with respect to the α- and β-receptors and

central nervous system depressant effect[60]

Antihypertensive activity of a series of 5-(alkyl and aryl)carboxamido

benzimidazole derivatives have been evaluated for in vitro angiotensin II ndash AT1 receptor

antagonism and in vivo by Dhvanit I Sha et al [61] Resulting that pharmacological

activities were inversely related to the size of alkyl and aryl substituents Thus the

compounds with lower alkyl groups at 5-position of benzimidazole nucleus demonstrated

potent antihypertensive activity

M Mandloi and coworkers [63] recently introduced an approach using Szeged

index (Sz) for the characterisation of Antihypertensive activity of 2-aryl-imino-

imidazolidines A comparison is made with the results obtained from the Wiener index

(W) Multiple regression analyses have shown that in this respect the Szeged index is

better than the Wiener index In an another approach RV Chikhale [62] Synthesize and

investigate antihypertensive activity of Fifteen new ethyl 6-methyl-2-methoxy-3-

(substituted 1-phenylethanone)-4-(substituted phenyl)-1 2 3 4-tetrahydropyrimidine-5-

carboxylates

The pharmacological activity of a series of substituted (E)-and (Z)-iminoethers of

18-naphthyridine from corresponding ketones was evaluated to assess the eventual

interaction with α and β adrenoceptors Result shows that all the compounds exhibited

β2 stimulating and β1 blocking properties while on α receptors neither stimulating nor

blocking activity was observed[64] A S Feliciano [65] prepared a novel kind of fused

heterocyclic compounds with the pyrido[21-b]oxazine ring and tested for their

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

Development 2011 1 85-104

11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 18: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

18

pharmacologic properties Some of them have shown long-term antihypertensive-

bradycardic effects as well as anti-inflammatory spasmolytic and other effects

Y Pore and coworkers [66] have done Quantitative structure activity relationship

(QSAR) studies on 5-cyano n1 6-disubstituted 2-thiouracil derivatives as central

nervous system depressants In another research E Arranz [67] have reported a novel

series of 23-dihydro-3-oxo-4H-thieno[34-e][124]thiadiazine 11-dioxides and their

pharmacological evaluation as drugs with effects on the rat cardiovascular system These

results suggest that like verapamil the cardiovascular effects produced by the new

thienothiadiazines seems to be due to a blockade of transmembrane voltage-dependent

calcium channels present in vascular smooth muscle cells and not to an activation of

ATP-sensitive K+ channels

In another approach by RK Russell et al [68] the cardiovascular evaluation of a

novel series of [4-alkyl(aryl)quinazolin-2-one-1-yl]alkanoic esters and acids (II) as renal

vasodilators was presented The compound 3-[67-dihydroxy-4-methyl-(1H)-

quinazoline-2-one-1-yl] propanoic acid was found to be a potent and selective renal

vasodilator

β-blocking activity of(R S)-(E)-oximeethers of 2 3-dihydro-18-naphthyridine

and 23-dihydrothiopyrano[2 3-b] pyridine potential antihypertensive agents have been

examined by P L Ferrarini et al[69]

A quantitative structure activity relationship (QSAR) analysis was carried out on

a series of 6-substituted benzimidazole derivatives to identify the structural requirements

for selective AT1 angiotensin antagonistic activity The QSAR expressions were

generated using 28 compounds and the predictive ability of the resulting model was

evaluated against a test set of 12 compounds showing geometrical structural and shape

descriptors governing the angiotensin II AT1 antagonistic activity [70]

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

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3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

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11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
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  • BM699037_ja
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Page 19: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

19

E G Chalina et al [71] prepared Some new 13-disubstituted ureas and phenyl

N-substituted carbamates and evaluated for their antiarrhythmic and hypotensive

properties in vivo The compound 1-tert-butyl-1-(3-cyclopentyloxy-2-hydroxypropyl)-3-

methylurea exhibited a strong hypotensive action

Genetic algorithm and multiple linear regression analysis were employed to select

an optimal combination of pharmacophoric models and physicochemical descriptors to

explore the structural requirements for potent renin inhibitors employing 119 known

renin ligands yielding self-consistent and predictive QSAR Successful pharmacophore

models were found to be comparable with crystallographically resolved renin binding

pocket[72]

Z Hernandez-Gallegos et al [73] evaluated nine new 14-dihydropyridines

(DHPs) in terms of relaxant activity the 4-(35-difluorophenyl) analogues were more

potent than those with 4-(4-fiuorophenyl) but weaker than those with 4-(3-nitrophenyl)

substituents while in terms of antihypertensive activity the 4-(35-difluorophenyl)

derivatives were more potent than their 4-(3-nitrophenyl) analogues

Based on the notion of a bioisosteric relationship indole and verapamil were

examined as calcium entry blockers and as alpha1-adrenoceptor antagonists in isolated

tissue preparations and as antihypertensive agents in the spontaneously hypertensive rat

Indole 27 exhibited potent calcium entry blockade in vitro and displayed antihypertensive

activityslightly less than verapamil However Indole 23 possessed both calcium entry

blockade and potent alpha1-adrenoceptor activity in vitro but in vivo was less active than

verapamil as an antihypertensive agent [74]

J Mungalpara et al [75] performed a quantitative structurendashactivity relationship

(QSAR) analysis on a data set of 104 molecules showing N-type calcium channel

blocking activity using several types of descriptors including electrotopological

structural thermodynamics and ADMET The genetic algorithm-based genetic function

approximation (GFA) method of variable selection was used to generate the 2D-QSAR

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

Development 2011 1 85-104

11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 20: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

20

model using five information-rich descriptorsmdashAtype_C_24 Atype_N_68 Rotlbonds

S_sssN and ADME_Solubilitymdashplaying an important role in determining N-type

calcium channel blocking activity

I Mudnic et al [76] described antioxidative and vasodilatory effects of phenolic

acids relating the number of hydroxyl groups in the phenyl ring degree of compactness

and branching of molecules and three-dimensional distributions of atomic polarisability

of the tested molecules by QSAR study

E Toja et al[77] have described that L 15848 (8b citrate) is a new anti-

hypertensive agent belonging to the class of 1-alkyl-2-aminoethylnaphth-[12-

d]imidazoles It lowers blood pressure in spontaneously hypertensive rats and in renal

hypertensive dogs Thus it can be concluded that the decrease in systolic blood pressure

is dose related and long lasting and is evident for periods of up to 7 h A slight and

transient decrease in heart rate was observed in the renal hypertensive dogs M Remko

[78 ] used the theoretical property to elucidate molecular properties of the

antihypertensive cardiovascular protective and antithrombotic perindopril The

calculations showed that l-arginine is bound to perindopril more strongly (by about

25 kJ molminus1

) than erbumine

Ulrike Unrig et al[79] described the molecular modeling and quantitative

structurendashactivity relationships (QSARs) studies on KATP channel openers (KCOs) of the

seven benzopyran varied at the C3- and C4-positions in order to understand which

molecular features at these positions are essentially effecting the biological activity The

study of impact of C6-substitution on biological activity using HANSCH analysis

concludes that a direct interaction between the C6-substituents and the receptor structure

is not of primary importance However the substitutents influence the orientation of the

whole ligand approaching the binding site An unfavorably oriented ligand cannot bind to

the binding site thus exhibiting weak activity A QSAR equation was developed showing

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

Development 2011 1 85-104

11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 21: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

21

a relationship between the vasodilator activity and the direction of the dipole vector of the

ligands

E K Bradley et al [80] have discovered new 3D computational approach to α1-

adrenergic receptor ligands lead evolution demonstrated for heterocyclic α1-adrenergic

receptor ligands to highly dissimilar active N-substituted glycine compounds based on

multiple pharmacophore hypothesesThis method is very rapid allowing very large virtual

libraries on the order of a million compounds to be filtered efficiently

W B Asher et al [81] have developed a two model system to mimic the active

and inactive states of a G-protein coupled receptor specifically the α1A adrenergic

receptor Two agonists epinephrine (phenylamine type) and oxymetazoline (imidazoline

type) as well as two antagonists prazosin and 5-methylurapidil have docked into two

α1A receptor models active and inactive The best docking complexes for both agonists

had hydrophilic interactions with D106 while neither antagonist donot possess such

activity

C Oefner [82] studied that aspartic proteinase 21ennin catalyses the first and rate-

limiting step in the conversion of angiotensinogen to the hormone angiotensin II and

therefore plays an important physiological role in the regulation of blood pressure

Agrawal Srivastava and Khadikar[83] have reported some interesting

topological models on Antihypertensive activity of a series of 4-(diarylmethyl)mdashN-

substituted piperidines using van der Waals volume (Vw) negentropy (N) and first -

order valence connectivity index (1X

v) The regression analysis of the data has shown that

statistically significant QSAR models were obtained in multiparametric correlations upon

addition of indicator parameters In an another approach Agrawal et al[84] have

reported their QSAR studies on a series of benzopyrans as potassium channel activators

using a large set of distance-based topological indices including the molecular descriptors

namely negentropy and molecular redundancyThe relaxant potency in rat trachea

expressed as pEC50 was used for biological characterization of the benzopyrans The

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

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understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

Development 2011 1 85-104

11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 22: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

22

results have shown that pEC50 can be modeled excellently in multiparametric model in

that we have to include an indicator parameter The predictive powers of the proposed

models were discussed on the basis of cross-validation parameters

JHierrezuelo and coworkers [85] have studied the antagonistic activity of

oligo(ethylene glycol)-alkene substituted theophyllines in positions 7 andor 8

derivatives by incorporating different group at different positions

D Lupei and L Minyong [ 86 ] reviewed the simulation of (α1-Ars) α1-adrenergic

receptors (therapeutic agent for hypertension ) and their interactions with antagonists by

using ligand-based (pharmacophore identification and QSAR modeling) and structure-

based (comparative modeling and molecular docking) approaches to understand the

structural basis of antagonist binding and the molecular basis of receptor activation thus

offering a more reasonable approach in the design of drugs targeting α1-Ars

Recently In addition to ACE ACE2 ndash which is a homolog of angiotensin

converting enzyme (ACE) and promotes the degradation of angiotensin II (Ang II) to

Ang (1ndash7) ndash has been recognized as a potential therapeutic target in the management of

cardiovascular diseases(CVDs) It also presents a new area for drug discovery in the

treatment of cardiovascular disease as well as in perinatal medicine and preventive

against diseases medicine of fetal origins[87]

QSAR modelling was done on series of compounds to find a more active and

selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues

Potassium (K(+)) channel openers are a diverse group of compounds which are used for

the treatment of diseases like angina pectoris hypertension congestive heart failure anti-

hypoglycemic (insulinoma) bronchial asthma etc RS-34-dihydro-22-dimethyl-6-halo-

4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-

sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-

cells [88]

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

Development 2011 1 85-104

11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

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14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 23: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

23

R M Touyz and AM Briones[89] reviewed Increased vascular production of

reactive oxygen species (ROS termed oxidative stress) is a multisystem phenomenon in

hypertension and involves the heart kidneys nervous system vessels and possibly the

immune system This review highlights the importance of ROS in vascular biology and

focuses on the potential role of oxidative stress in human hypertension

JZ Sun et al[90] studied that long term use of ACE inhibitors provides

cardiovascular protection and reduce ischemic events and complications independent of

their effect on heart function and blood pressure It also produces remarkable survival and

heart function benefits in patients with acute myocardial infarction ACE blockage can

prevent or delay the development or progression of renal disease at all stages from

subclinical micro albuminuria to end-stage renal disease In another study increased

plasma aldosterone concentration (PAC) is associated with impaired cognitive function

and mineral corticoid receptor blockade may protect against not only cardiovascular

mortality but also cognitive impairment in patients with hypertension [91]

A randomized clinical trial of losartan and ramipril on adipose tissue activity and

vascular remodeling biomarkers was done in hypertensive patients to evaluate whether an

antihypertensive intervention at the proximal or distal level of the 23enninndashangiotensinndash

aldosterone system could have different effects on a broad range of innovative

cardiovascular risk biomarkers shows that short-term treatment with losartan improved

several metabolic parameters in hypertensive subjects whereas ramipril did not[92]

The Renin-Angiotensin System (RAS) is pivotal in the regulation of blood

pressure and electrolyte balance Angiotensin-Converting Enzyme (ACE) plays a crucial

role in the RAS by the production of a potent vasoconstrictive octapeptide angiotensin II

which affects peripheral resistance renal function and cardiovascular structure [93]

ACE is a chloride-dependent zinc metallopeptidase that contains 1277 amino acid

residues and has two homologous domains each with a catalytic site and a region for

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

Development 2011 1 85-104

11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 24: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

24

binding Zn++

It is non-specific and cleaves dipeptide units from substrates with

diverse amino acid sequences Bradykinin is one of the many natural substrates for ACE

whose inactivation by ACE further contributes to hypertension [94]

Since the development of first marketed ACE inhibitor captopril these agents

have become the first-line agents for the treatment of hypertension and a variety of

cardiovascular disorders including heart failure left ventricular hypertrophy post

myocardial infarction chronic kidney diseases (including diabetic and non-diabetic

nephropathy) and proteinuria [95] As a summary of evidence from clinical trials it is

reported that treatment with ACE inhibitors has a beneficial role in patients selected for

the treatment of left ventricular dysfunction after Acute Myocardial Infarction (AMI) and

in relatively unselected patients with AMI [96] Several clinical trials have been

performed to study the beneficial effects of ACE inhibitors on diabetes mellitus induced

AMI and it was found that apart from the beneficial effects in vascular remodeling they

also reduced recurrent ischemic events after myocardial infarction[97] ACE inhibitors

are more effective than any other antihypertensive drug in treating chronic renal diseases

even in normotensive patients [98] A brief report of a patient with congenital nephrotic

syndrome (development of nephrotic syndrome in the first three months of life) of

unusual etiology suggested responsiveness to an ACE inhibitor alone (captopril) [99] A

brief review of literature cited above clearly shows the superiority of ACE inhibitors for

the treatment of cardiovascular diseases

QSAR models are mathematical equations which try to correlate the structural and

chemical characteristics of drug molecules with their biological activities Once the

relationships are established the information helps in rationally designing more potent

compounds and the predictions of biological activities can be done for many new

compounds as suggested by several researchers [100-103]

Various N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl] amino acids

derivatives have been designed synthesized and evaluated in vitro and in vivo as ACE

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

Development 2011 1 85-104

11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 25: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

25

inhibitors [104]One of the active member of the series of compounds used in the present

study is (S)-N-cyclopentyl-N-[3-[(22-dimethyl-1-oxopropyl)thio]-2-methyl-1-

oxopropyl]glycine (pivopril or pivalopril) having potency lower than that of captopril

[105]This prompted us to further explore glycine based ACE inhibitors

A hypothetical receptor surface model has been constructed for a set of 38 AT1

antagonists using activity data of each molecule as a weight in the building of the

receptor surface The best model was derived by optimizing various parameters such as

atomic partial charges surface fit and the manner of representation of electrostatics on

the surface using van der Waals energy electrostatic energy and total nonbonded energy

as descriptors individually or in combination to derive a family of quantitative structure -

activity relationship equations with GPLS as the statistical method[106]

15 Aim of Present Investigation

The aim of present work is to theoretically design some new potent

antihypertensive drugs We have therefore planned to develop several QSAR models

for activities of few drugs molecules The biological activities will be correlated with

each of the following topological indices and the correlation will be subjected to

regression analysis using the method of least squares[107-108]which can be used to

predict the activity of new drugs The information obtained will be used by the synthetic

chemists in synthesizing new potent antihypertensive drugs

The topological indices such as W J JhetZ Jhetm Jhetv Jhete Jhetp BAC

0

1

2

3

0

v

1

v

2

v

3

v etc have been used for the QSAR modeling

The above mentioned study will be carried out for the following different types of

antihypertensive drugs

1 Calcium channel antagonists

2 Angiotensin II antagonists

3 Pancreatic β-cells KATP channel openers

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

Development 2011 1 85-104

11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 26: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

26

REFERENCES

1 C Hansch D Hoekman H Gao Comparative QSAR toward a deeper

understanding of chemicobiological interactions Chem Rev 1996 96 1045ndash

1076

2 C Hansch A Leo Exploring QSAR Fundamentals and Applications in

Chemistry and Biology ACS Publishers Washington DC 1995

3 T Pandya S K Pandey MTiwari S C Chaturvedi Anil K Saxena Bio Med

Chem 2001 9(2) 291-300

4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T

Inagami Regulatory Peptides 2001 102( 1) 41-47

5 K Song N Shiota S Takai HTakashima H Iwasaki S Kim and M Miyazaki

Atherosclerosis 1998 138( 1) 171-182

6 CSkold and A Karleacuten Journal of Molecular Graphics and Modelling2007 26(

1) 145-153

7 S Takami T Katsuya H Rakugi N Sato YNakata A Kamitani T Miki J

Higaki and T Ogihara American Journal of Hypertension1998 11( 3) 316-321

8 L Daviet JY A Lehtonen W Hayashida V J Dzau and M Horiuchi Life

Sciences 2001 69(5) 509-516

9 GBerglund O Andersson The Lancet1981 317( 8223) 744-747

10 S KPaliwal A Pandey and SPaliwal American Journal of Drug Discovery and

Development 2011 1 85-104

11 C H Gelband C Sumners D Lu and M K Raizada 1997 72 (2-3) 139-145

12 VA Ashwood FCassidy MCColdwell JM Evans TC Hamilton DR

Howlett DMSmith and GStemp JMedChem1990332667

13 H M Siragy American Journal of Hypertension 2002 15( 11)1006-1014

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 27: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

27

14 JR Shanklin P Shristopher Johnson III GP Anthony and JB Richard

JMedChem 1998 31 902

15 V Nand SA Doggrell Jpharmacology199951631-641

16 L Jennifer Wilkinson-Berka The International Journal of Biochemistry amp Cell

Biology2006 38( 5-6) 752-765

17 K Asano W Minobe K D Mitchusson D Dutcher R L Roden J David Port

M R Bristow J Am College of Cardiology199525(2) 291A-292A

18 K S Jain J B Bariwal M K Kathiravan M S Phoujdar Rajkumari S Sahne

B S Chauhan A K Shah and M R Yadav Bio Med Chem200816( 9)

4759-4800

19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140

20 V Alagarsamy and U S Pathak Bio Med Chem 2007 15 ( 10) 3457-3462

21 S V Bhandari K G Bothara AA Patil T S Chitre A P Sarkate S T Gore

S C Dangre and C V Khachane Bio Med Chem200917( 1) 390-400

22 T Mavromoustakos P Moutevelis-Minakakis

CG Kokotos P Kontogianni A

Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E

Iliodromitis Bio Med Chem 200614(13) 4353-4360

23 B Hemmateenejad R Miri M Akhond MShamsipur Chemometrics and

Intelligent Laboratory Systems200264(1) 91-99

24 JC Liang JL Yeh CSWang SFLiou CH Tsai and IJ Chen Bio Med

Chem200210( 3) 719-730

25 S B Etcheverry E G Ferrer L Naso D A Barrio L Lezama T Rojo and P

AM Williams Bio Med Chem2007 15(19) 6418-6424

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 28: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

28

26 LW Wang JJ Kang IJ Chen CM Teng and CN Lin

Bio Med

Chem2002 10( 3) 567-572

27 SD Kimball J T Hunt J C Barrish J Das D M Floyd M W Lago V G

Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and

W F Lau Bio Med Chem1993 1( 4) 285-307

28 N Kaur A Kaur Y Bansal D I Shah G Bansal and M Singh Bio Med

Chem2008 16( 24) 10210-10215

29 R P Verma A Kurup S B Mekapati and CHansch

Bio Med Chem2005

13(4) 933-948

30 R P Bhole K P Bhusari 2011 344 (2) 119ndash134

31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio

Med Chem 20008( 6) s 1393-1405

32 J B Press J J McNally P J Sanfilippo M F Addo D Loughney EGiardino

L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435

33 JT Nguyen C A Velaacutezquez and E E Knaus Bio Med Chem 200513( 5)

1725-1738

34 J C Barrish S H Spergel S Moreland G Grover SA Hedberg A T

Pudzianowski JZ Gougoutas and M F Malley Bio Med Chem1993 1( 4)

309-325

35 W L Cody DD Holsworth N A Powell M Jalaie E Zhang WWang B

Samas JBryant ROstroski M J Ryan and J Edmunds Bio Med Chem2005

13( 1) 59-68

36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E

M Gordon Bio Med Chem1998 (7) 883-889

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 29: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

29

37 A Vermeulen A Wester PF A Willemse F A T Lustermans C J Stegeman

J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45

38 T Pandya S K Pandey M Tiwari S C Chaturvedi AK Saxena Bio Med

Chem 2001 9( 2) 291-300

39 M Remko M Swart and F M Bickelhaupt Bio Med Chem200614( 6)

1715-1728

40 H Zong Si TWang K J Zhang Z D Hu and BT Fan Bio Med Chem2006

14(14) 4834-4841

41 XZ Guo LShi RWang XX Liu BGang Li and XXia Lu Bio Med

Chem2008 16( 24) 10301-10310

42 S Demirayak AC Karaburun and R Beis Euro J of Med Chem2004 39(

12) 1089-1095

43 C Caveacute H Galons M Miocque P Rinjard G Tran and P Binet Euro J Med

Chem1994 29( 5) 389-392

44 V K Agrawal P V Khadikar Oxi Commun2003 26 1-8

45 A A Siddiqui R Mishra and M Shaharyar Euro J Med ChemArticle in

Press Corrected Proof - Note to users

46 P Maacutetyus

J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G

Rabloczky L Jaszlits E Horvaacuteth Z Toumlmoumlskoumlzi G Cseh E Horvaacuteth and P

Araacutenyi Euro J Med Chem1992 27( 2) 107-114

47 G Cignarella D Barlocco MM Curzu GA Pinna P Cazzulani M Cassin

and B Lumachi Euro J Med Chem 199025(9) 749-756

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 30: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

30

48 J D Marsh M A M Dionne MChiu and T W Smith J Mol and

CellCardiology1988 20( 12) 1141-1150

49 B M Massie J F Tubau J Szlachcic CVollmerThe American Journal of

Cardiology 1986 58( 8 ) D16-D19

50 A Leonardi G Motta R Pennini RTesta GSironiA Catto A Cerri M

Zappa G Bianchi and D Nardi Euro J Med Chem1998 33(5) 399-420

51 JP Bonte MC Piancastelli I Lesieur JC Lamar M Beaughard and G

Dureng Euro J Med Chem1990 25( 4)361-368

52 F G McMahon The Am Jof Cardiology 198658( 8) D8-D11

53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G

Bruni and G SegreEuropean Journal of Medicinal Chemistry1991 26( 4) 381-

386

54 Q Su L Zhou J Mol Model 2006 12 869ndash875

55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L

Antkiewicz-Michaluk Euro J Med Chem2002 37(3) 183-195

56 M Badawneh P L Ferrarini VCalderone C Manera E Martinotti Claudio

Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)

925-934

57 GA Pinna MM Curzu G Cignarella D Barlocco M DAmico A Filippelli

V De Novellis and F Rossi Euro J of Med Chem 1994 29(6) 447-454

58 K Kulig J Sapa A Nowaczyk BFilipek and B Malawska Euro J of Med

Chem2009 44(10) 3994-4003

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 31: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

31

59 A Ma Velaacutezquez L Martiacutenez V Abrego MA Balboa LA Torres B

Camacho S Diacuteaz-Barriga A Romero R Loacutepez-Castantildeares and E Angeles

Euro J of Med Chem2008 43( 3)486-500

60 SBotros and S F Saad Euro J of Med Chem 1989 24( 6) 585-590

61 D I Shah MSharma Y Bansal G Bansal and M Singh Euro J Med Chem

200843( 9) 1808-1812

62 RV Chikhale RP Bhole PB Khedekar and KP Bhusari Euro J Med Chem

200944(9) 3645-3653

63 M Mandloi V K Agrawal K C Mathur P V Khadikar and S Karmarkar

Oxid Comm 2002 25 193

64 PL Ferrarini C MoriG Primofiore A Da Settimo MC Breschi E

Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496

65 A San Feliciano E Caballero P Puebla JAP Pereira J Gras and C Valenti

Euro J Med Chem 1992 27(5) 527-535

66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and

Biostructures 2009 4(2) 373 ndash 382

67 E Arranz J A Diacuteaz S Vega M Campos-Toimil F Orallo I Cardeluacutes JLlenas

and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759

68 RK Russell MA Appollina V Bandurco DW Combs RM Kanojia R

Mallory E Malloy JJ McNally DM MulveyY Gray-NunezMS

RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC

Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 32: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

32

69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera

AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)

815-826

70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565

71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem

199833(12) Pages 985-990

72 Al-Nadaf AH Taha MOJ Mol Graph Model 201129(6)843-64

73 ZHernaacutendez-Gallegos PA Lehmann F E Hong F Posadas and E Hernaacutendez-

Gallegos Euro J Med Chem1995 30(5) 355-364

74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med

Chem 1990 25( 2) 191-196

75 J Mungalpara A Pandey V Jain and C Gopi Mohan Journal of Molecular

Modeling 16( 4) 629-644

76 IMudnic D Modun VRastija J Vukovic I BrizicV Katalinic B Kozina

M Medic-Saric and M Boban Food Chemistry 2010 119( 3) 1205-1210

77 E Toja G Di Francesco D Barone EBaldoliN Corsico and G Tarzia Euro

J Med Chem1987 22(3) 221-228

78 M Remko Euro J Med Chem2009 44(1)101-108

79 U Uhrig H-D H Raimund Mannhold H Weber and H Lemoine Journal of

Molecular Graphics and Modelling2002 21(1)37-45

80 E K Bradley P Beroza J E Penzotti P D J Grootenhuis D C Spellmeyer

and J L Miller Med Chem 2000 43 (14) 2770ndash2774

81 W B Asher SN Hoskins L A Slasor D H Morris E M Cook and DL

BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912

33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
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33

82 C Oefner A Binggeli V Breu D Bur J-P Clozel A DArcy A Dorn W

Fischli F Gruumlninger R Guumlller G Hirth HP Maumlrki SMathews M

Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W

Wostl Chem amp Bio 1999 6(3) 127-131

83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-

130

84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT

Supuran Euro J Med Chem2006 41( 3)360-366

85 J Hierrezuelo J Manuel Lopez-Romero R Rico J Brea M Isabel Loza CCai

and MAlgarra Bio Med Chem2010 18(6) 2081-2088

86 D Lupei L Minyong Curr Comp ndash Aided Drug Des2010 6(3) 165-178(14)

87 LShi C Mao Z Xu and L ZhangDrug Discovery Today 201015(9-10) 332-

341

88 SkM Alam S Samanta AK Halder S Basu T Jha Euro J of

medchem 2009 44(1) 359-64

89 R M Touyz and AM Briones Hyper Res 2011 34 5ndash14

90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22

91 S Yagi M Akaike Kichi Aihara T Iwase S Yoshida Y Sumitomo-Ueda

Y Ikeda K Ishikawa T Matsumoto and MSata HyperRes 201134 74ndash78

92 G Derosa P Maffioli IFerrari IPalumbo SRandazzo E Fogari A D Angelo

and A FG Cicero Hyper Res 2011 34 145ndash151

93 EK Jackson Renin and Angiotensin In Goodman and Gilmans the

Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG

Gilman (Eds) 200110th Edn McGraw-Hill New York pp 809-829

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 34: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

34

94 A Kuoppala KA Lindstedt J Saarinen PT Kovanen and JO Kokkonen Am

J Physiol Heart Circ Physiol 2000 278 H1069-H1074

95 M SuttersSystemic Hypertension In Current Medical Diagnosis and Treatment

McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New

Jersey 2008 pp 371-399

96 R Latini AP Maggioni M Flather P Sleight and G Tognoni ACE inhibitor

use in patients with myocardial infarction Summary of evidence from clinical

trials Circulation 199592 3132-3137

97 RW Nesto and S Zarich Acute myocardial infarction in diabetes mellitus

Lessons learned from ACE inhibition Circulation 1998 97 12-15

98 AB Fogo Curr Hypertens Rep 1999 1 187-194

99 R Shreedharan and D Bockenhauer Pediatr Nephrol 2005 201340-1342

100 A Jamloki C Karthikeyan SK Sharma NSHN Moorthy and P Trivedi

Asian J Biochem 20061 236-243

101 T Abhilash M Thakur and S Thakur Asian J Biochem 2006 1 138-147

102 C Karthikeyan PM Kumar NSHN Moorthy SK Shrivastava and T Piyush

Asian J Biochem 20061307-315

103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336

104 SK Panday M Dikshit and DK Dikshit Med Chem Res 200918 566-578

105 R Kumar R Sharma K Bairwa RK Roy A Kumar and A Baruwa Der

Pharmacia Lett 2010 2 388-419

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja
Page 35: CHAPTER -1 INTRODUCTION - Shodhgangashodhganga.inflibnet.ac.in/bitstream/10603/25218/6/06_chapter-1.pdf · CHAPTER -1 INTRODUCTION Quantitative structure–activity relationship (QSAR)

35

106 P A Datar P V Desai E C Coutinho J Che Inf and Comp Sci 2004 44( 1)

210-220

107 P V Khadikar S Sharma S Joshi I Lukovitz M Kaweeshwar Bull Soc

Chem Belg1992 106 767

108 I Gutman OE Polansky Springer Verlag Berlin (1986)

  • sec07_ch071_ch071a_347
  • sec07_ch071_ch071a_346
  • sec07_ch071_ch071a_349
  • sec07_ch071_ch071a_348
  • bvt1
  • hit2
  • hit6
  • bcor_
  • bvt2
  • bvt3
  • bvt4
  • bvt5
  • bvt6
  • bvt7
  • bvt8
  • bcorr1
  • m4_bcor_
  • au2
  • au3
  • au4
  • au5
  • au6
  • au9
  • au10
  • bfnfn2
  • bcor1
  • bfn1
  • BM691755_ja
  • BM23227_bc
  • BM691756_ja
  • BM691767_ja
  • BM691705_ja
  • BM691785_ja
  • BM112632_ja
  • BM112590_ja
  • BM112663_ja
  • BM113292_ja
  • BM699037_ja
  • BM699023_ja