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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
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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and B Lumachi Euro J Med Chem 199025(9) 749-756
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55 B Malawska K Kulig B Filipek JSapa D Maci g M Zygmunt and L
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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
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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
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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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Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496
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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
Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284
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AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)
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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
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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
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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
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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
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-
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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J Kosaacutery E Kasztreiner N Makk E Diesler K Czakoacute G
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and B Lumachi Euro J Med Chem 199025(9) 749-756
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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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Mori G Saccomanni and L Testai Euro J of Med Chem2001 369 (11-12)
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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
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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
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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
66 Y Pore B Kuchekar M Bhatia K Ingle Digest Journal of Nanomaterials and
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
Giardino R Falotico and AJ TobiaEuro J Med Chem199227(3) 277-284
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69 P L Ferrarini C Mori MBadawneh V Calderone RGreco CManera
AMartinelli P Nieri and G Saccomanni Euro J Med Chem2000 35( 9)
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70 A Jain SC Chaturvedi Sci Pharm 2009 77 555ndash565
71 E G Chalina L Chakarova and D T Staneva Euro J Med Chem
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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
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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
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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-
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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
-
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 A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759
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RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC
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74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med
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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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84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT
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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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90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22
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and A FG Cicero Hyper Res 2011 34 145ndash151
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Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG
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McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New
Jersey 2008 pp 371-399
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Lessons learned from ACE inhibition Circulation 1998 97 12-15
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Asian J Biochem 20061307-315
103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336
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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
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-
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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4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T
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Chem2002 10( 3) 567-572
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Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and
W F Lau Bio Med Chem1993 1( 4) 285-307
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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
Med Chem 20008( 6) s 1393-1405
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L B Katz R Falotico B J Haertlein Bio Med Chem1993 1( 6) 423-435
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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
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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
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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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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
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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
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
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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
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)
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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
-
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
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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
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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
-
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
-
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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Politi P Zoumpoulakis J Findlay A Cox A Balmforth A Zoga and E
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Lee S H Spergel S Moreland SA Hedberg JZ Gougoutas M F Malley and
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Bio Med Chem2005
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31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio
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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
-
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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Martinotti P Nieri and MA Ciucci Euro J Med Chem 1990 25( 6)489-496
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and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759
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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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74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med
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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
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BautistaJ Chem Inf Model 2007 47 (5) 1906ndash1912
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Muumlller RG Ridley H Stadier E Vieira M Wilhelm FK Winkler and W
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83 VK Agrawal R C Srivastava and P V Khadikar Acta Pharma 200151117-
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84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT
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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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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
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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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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
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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
-
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
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Atherosclerosis 1998 138( 1) 171-182
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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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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
-
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 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
-
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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1076
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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
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15 V Nand SA Doggrell Jpharmacology199951631-641
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Biology2006 38( 5-6) 752-765
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M R Bristow J Am College of Cardiology199525(2) 291A-292A
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4759-4800
19 K Nikolic S Filipic and D Agbaba BioMed Chem 2008 16(15) 7134-7140
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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
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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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Bio Med
Chem2002 10( 3) 567-572
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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
-
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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Oxid Comm 2002 25 193
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and A G Fernaacutendez Euro J Med Chem2000 35( 7-8) 751-759
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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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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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Modeling 16( 4) 629-644
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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
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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
-
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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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
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
-
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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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
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Atherosclerosis 1998 138( 1) 171-182
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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
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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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
-
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
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RampullaRA Rampulla SA Sisk L Williams SD Levine SC Bell EC
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74 R M Soll J A Parks T J Rimele R J Heaslip AWojdan Euro J Med
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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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84 V K Agrawal JSingh M Gupta YAli Jaliwala P V Khadikar and CT
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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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90 JZ Sun LH Cao and H Liu Hyper Res 2011 34 15ndash22
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and A FG Cicero Hyper Res 2011 34 145ndash151
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Pharmacologic Basis of Therapeutics Hardman JG LE Limberd and AG
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McPhee SJ MA Papadakis and LM Tierney (Eds) McGraw-Hill New
Jersey 2008 pp 371-399
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Lessons learned from ACE inhibition Circulation 1998 97 12-15
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Asian J Biochem 20061307-315
103 A Jain and SC Chaturvedi Asian J Biochem 2008 3 330-336
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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
-
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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36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E
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J H B de Bruijn The American Journal of Medicine 1988 84( 3) 42-45
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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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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
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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
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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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53 V Cecchetti F Schiaffella O Tabarrini W Zhou A Fravolini A Goi G
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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
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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
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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
-
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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29 R P Verma A Kurup S B Mekapati and CHansch
Bio Med Chem2005
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31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio
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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
-
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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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
-
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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31 N Taka H Koga H Sato T Ishizawa T Takahashi and Jichi Imagawa Bio
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36 M F Gordeev DV Patel BP England S Jonnalagadda J D Combs and E
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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
-
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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M R Bristow J Am College of Cardiology199525(2) 291A-292A
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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
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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
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Chem2002 10( 3) 567-572
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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
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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
-
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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4 J M Saavedra IArmando JA Terron A Falcon-Neri O Joumlhren WHaumluser T
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4759-4800
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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
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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
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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
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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
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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
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-
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
-