Medicinal Chemical Introduction

8/18/2019 Medicinal Chemical Introduction

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Medicinal Chemistry


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all material is available online as pdf filesunder the following URL:

http://www.chem.uzh.ch/zerbe/MedChem/Course_MedChem.html


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The Medicinal Chemistry Course• ADME (adsorption, distribution, metabolism and excretion) of drugs

• drug-receptor interactions

• development of drugs

• screening techniques

• combinatorial chemistry (D.O.)

• classical medicinal chemistry, hit-to-lead development

• fragment-based drug design

• rational drug design / de-novo drug design

• natural products

• case studies of drug synthesis (D.O.)

• the common targets for drugs (receptors)

• biophysical methods for determination of structure and binding interactions

• antibacterial drugs

• antiviral drugs

• anti-cancer drugs

• anti-inflammatory drugs

• patent issues (P.F.)


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Books and other information sources

Monographs:

• G. Patrick: Introduction to Medicinal Chemistry, Oxford University Press, 2005

(very good introduction)

• H.-J. Böhm, G. Klebe, H. Kubinyi: Wirkstoffdesign. Der Weg zum Arzneimittel

(Spektrum Lehrbuch) (very interesting, easy to read)

• G. Thomas: Medicinal Chemistry: An Introduction (Wiley), (inexpensive introduction)

• H. P. Rang, M. M. Dale, J. M. Ritter: Pharmacology, Churchill Livingstone; 6th ed.

• E.J. Corey, B. Czakó, L. Kürti, Molecules and Medicine (Wiley)

• D.S. Johnson, J.J. Li: The Art of Drug Synthesis (Wiley)

Journals:

• Nature Reviews Drug Discovery

• Drug Discovery Today

• ACS Journal of Medicinal Chemistry

• Trends in Pharmacological Sciences


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age

quality of

life

childbed feverof the mother

1

1 infection of appendix

2

2

3

accidents3

Society before 1800


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1

1

2

2

3

3

Medicine ca. 1950

asepsis

anesthesia,

antibiotics

vaccination

age

quality of

life

childbed feverof the mother

infection of the appendix

accident tetanus


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Medicine after ~ 1950

age

quality of

life


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8

most common cause of death for 22-44 year old people


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65 years and older...

!""#

Arteriosclerosis

Cardiac Infarction

Lung Cancer

(smokers lung)obstructive lung disease

Prostate Cancer

Pneumonia

Colon Cancer

Pancreatic Cancer

9,7%

7,7%

6,9%

4,7%

3,8%

3,7%

2,9%

2,8%

2,4%

1,7%

9,8%

8,3%

6,1%

4,3%

3,5%

3,0%

2,7%

2,3%

2,1%

2,1%

hypertension-relatedheart condition

Breast cancer

Cardiac arrhythmia

Male Female

Cardiac insufficiency

Stroke

Arteriosclerosis

Cardiac Infarction

Lung Cancer

Stroke Pneumonia

(smokers lung)obstructive lung disease

Cardiac insufficiency


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Medicine in the antiquity

• Chinese medicine: (3500 BC)

– chinese herbs, some of the ingredients are still in use today, e.g.

Reserpin (blood high pressure; emotional and mental control), Ephedrine(Asthma)

• Egyptian medicine (3000 BC)

– Papyrus Ebers, 877 descriptions and recipes

• Greek medicine (from 700 BC)– illness is no punishment from God, medicine is considered a science

– diseases are due to natural causes

– Hippocratic oath

• Roman medicine (from approx. 200 BC):

– invention of hospitals

– large influence of greek medicine

– Materia Medica: pharmaceutical descriptions


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Medicine in the Middle Ages (400 to 1500 AC)

• The church preserves greek traditional recipes• Era of horrible epidemics (e.g. Pest, Lepra, Pox, Tuberculosis)• Arabic medicine: Development of medical procedures for drug preparation

(distillation)

afterwards....

• Development of scientific approaches:

• Pox: Edward Jenner discovered that people who worked withcattle and had caught the cowpox disease (a mild diseaserelated to smallpox) were immune and never caught smallpox. Heinoculated a boy with blister fluid from a woman with cowpox.He later inoculated the same boy with fluid from smallpox, anddiscovered that the boy was immune against the disease.

• Bill Withering introduces extracts of Digitalis for treatment ofheart problems

• Louis Pasteur discovers that microorganisms are responsiblefor diseases and develops vaccinations against rabies. Heintroduces attenuated viruses for treatment of rabies.


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until 1900

• Digitalis (isolated from the plant digitalis, stimulation ofthe heart muscle)

• Chinin (alkaloid from peruvian bark, treatment of malaria,

fever lowering)

• Ipecacuanha (from the bark of ipecac, treatment of

diarrhea)

• Aspirin (from the meadow bark, against fever and pain)

• Mercury (-> syphilis)

12


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Discovery of Penicillin

• Alexander Flemming discovers in 1928 that a fungus grew on a

bacterial plate containing staphylococci. Close to the fungus allbacteria were killed.

• Biotechnological production of penicillins was established

during the second world war and helped saving the life of many

soldiers

13


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Robert Koch

Nobel laureate 1905"for his discovery and treatment oftuberculosis"

B t i d th l t i


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Pseudomonas Aeruginosa

Bacteria under the electron microscopeEscherichia Coli

Cholera

Stapphylococcus Aureus


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Since then....

• Early 1900: synthetic drugs, foundation of pharmaceuticalindustry

• since 1930: screening of natural products, isolation of their

bioactive ingredients

• late 70 ies: Development of recombinant drugs (proteins, e.g.interferons). Development of biotechnology

• 2000: Deciphering of the human genom, gene therapy (?),Investigation of the molecular basis of disease

• future: Personalized medicine?


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C o m p

l e x i t y

accidentialobservation

focus on

biochemistry

focus on

cell-biology

focus on

molecular function

History of drug development

taken from: Real World Drug Discovery, R. Rydzewski, Elsevier 2008


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Blockbuster (2004)

Best-selling pharmaceutical products 2002–2004

Sales figures for 2002

(US$ billion)


(US$ billion)


(US$ billion)

Product

Trade (Generic) name

Company

Company IMS Company IMS Company IMS

Lipitor (Atorvastatin) Pfizer 7.90 8.60 9.23 10.3 10.86 12.00

Zocor (Simvastatin) Merck 5.60 6.20 5.01 6.10 5.20 5.90

Plavix (Clopidrogrel) BMS and Sanofi-Aventis 3.10 NA 4.20 3.70 5.20 5.00

Advair (Fluticasone; Salmetrol) GSK 2.00 NA 3.60 NA 4.50 4.70

Norvasc (Amlodipine) Pfizer 3.80 4.00 4.33 4.50 4.46 4.80

Zyprexa (Olanzapine) Eli-Lilly 3.60 4.00 4.27 4.80 4.42 4.80

Paxil (Paroxetine) GSK 1.90 NA 3.00 3.90 3.90 3.90

Nexium (Esomaprazole) AstraZeneca 1.97 NA 3.30 3.80 3.88 4.80

Zoloft (Sertraline) Pfizer 2.74 NA 3.10 3.40 3.36 NA

Celebrex (Celecoxib) Pfizer 3.00 NA 1.90 2.50 3.30 NA

Effexor (Venlafaxine) Wyeth 2.00 NA 2.70 NA 3.30 3.70

Prevacid (Lansoprazole) Takeda and Abbott 3.70 3.60 3.30 4.00 3.10 3.80

Diovan (Valsartan) Novartis 1.66 NA 2.50 NA 3.10 NA

Fosamax (Alendronate) Merck 2.20 NA 2.50 NA 3.10 NA

Risperdal (Risperidone) J&J 2.10 NA 2.50 NA 3.00 NA

Global pharma market IMS US$550 billion; global biotechnology market valued at US$55 billion; global generic market US$62 billion.

Table lists top 15 Medicines in 2004 with sales of over US$3 billion.

Abbreviations: BMS, Bristol-Myers Squibb; GSK, GlaxoSmithKline; J&J, Johnson and Johnson; NA, not available.

• cholesterol-lowering medication

• lipid-lowering agent• anti-platelet medication

• anti-asthma medication

• blood pressure-lowering agent

• anti-depressant

• anti-depressant

• decreases the amount of acid produced in the stomach

• anti-depressant

• anti-inflammatory drug• anti-depressant

• decreases the amount of acid produced in the stomach

• prevents vasoconstriction

• anti-osteoporosis agent

• antipsychotic medication


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Blockbusters 2013 (C&N news, supl. 09/14)


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Top small molecule drugs

Salmeterol

(CH2)6

(CH2)4

HO

HO

OH

ONH

Rosuvastatin

CH3

CH3

H3C

H3C

HO2C

HO

OH

N

F

N

O O

S

N

SitagliptinCF

3

NH2 O

N

N

N

N

F

F

F

Imatinib mesylate

CH2

H3C

N

N

C

O

NH

CH3

N

N

NH

N

Aripiprazole

(CH2)4

ClCl

O

O

HN

N

N

Duloxetine

CH3NH

OS

Pregabalin

CH3

H3C

CO2H

NH2

Lenalidomide

NH2

HN

N

O

O

O

Tiotropium bromide

CH3

CH3

O

O

S

+N

Br -

S

O

HO

Esomeprazole

OCH3

CH3

CH3O

CH3

S

N

N

HN

O

Valsartan

CH3

CH3

HO2C

N

N

NNH

N

O

Budesonide

H3C CH

3

O

O

O

O

HO

HO

H

H

H

H

Formoterol

CH3O

CH3

NH

OH

OH

OHC

NH

Tenofovir

NH2

CH3

PO3H

2

N

N

N O

N

Celecoxib

NH2

F3C

O

O

S

NN

CH3

Telmisartan

N

N

N

N

CH3

HO2C

CH3

CH2


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predicted blockbusters (sales started/start soon)

http://www.ibtimes.com/11-blockbuster-drugs-watch-2015-1857100


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Properties of typical drugs

• small, organic molecules (Lipinski’s Rule of Five):molecularweight < 500, not too polar, not too manyfunctional groups that can serve as H-bond donors or

acceptors• or: natural products

• chemical synthesis should be not too complicated (price!)

•no reactive groups in the molecule


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Typical drugs

Indinavir

N

N

N

H

N

OH OH

O NHO

N

N

O

S

HO O

NH2

Lamivudine

O

N O

N

N

NH

O

F

Cl

Gefitinib

N

O

F

N

HN

COOH

Ciprofloxacin

N

NS

O

N

HNN

N

O

O O

H3C

CH3

SildenafilLinezolid

O

N

NO

F

O

H

H

N

O

NS

HN

NH

O

H H

COOH

HO H

Imipenem

N NO

S

NH

O

O

CH3

Rosiglitazone

Atorvastatin

N

F

N

H

OH OHO

COOH


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Blockbusters are often similar....

Figure 8. Structural similarity in blockbusters. Examples of structural similarities between

compounds within a given class: 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase

inhibitors (lovastatin and simvastatin), angiotensin II antagonists (losartan and valsartan),

and proton-pump inhibitors (omeprazole and lansoprazole).

DDT Vol. 7, No. 10 May 2002

O

HO OChiral

O

O

Lovastatin

NH

NN

NN

N

Cl

HO

LosartanO

Me N

HN

S

O

N

O MeOmeprazole

OH

OO

HO OChiral

Simvastatin

NHN

N

N

N

O

O

HO

Valsartan Drug Discovery Today

N

HN

SN

O

F

F

FO

Lansoprazole


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Recombinant Drugs

SUPPLEMENTARY INFORMATION "# $%&'() *&%+,-.- /0 1%%-'(# 234567869 :;;


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Portfolio share of biologics


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Derivates of Natural Products


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Gleevec: Target Identification

• Identification of an oncogene (a gene that results in increases

tumorgenic activity):

– chronic myelogenous Leukaemia is characterized by excessive

proliferation of certain cells

– CML results from gene translocation between chromosomes 9and 22

– as a result a BCR-ABL gene is created, that encoded for the

BCR-ABL kinase

– The sole expression of the BCR-ABL gene is identified as thesole oncogenic event resulting in induction of Leukaemia in mice.

Capdeville, Nat.Rev.Drug.Discov. 1 (2002),493


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Gleevec: Medicinal Chemistry

• Lead compound identified from screen for inhibitors ofthe protein kinase C (PCK). Strong binding is retained when

the pyridyl unit is added.

• Presence of an amide group on the phenyl ring providedinhibitory activity against tyrosine kinases such as BCR-ABLkinase (target hopping)

• Substitution at position 6 of the diaminophenyl ringabolished PCK inhibitory activity while retaining it attyrosine kinases (increasing selectivity)

• Improvement of ADME properties. Addition of a polarside-chain markedly increases both solubility and oralbioavailability. To avoid the mutagenic potential of anilinecompounds a CH2 spacer was inserted.



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• the structures of active kinases are

similar. Hence it is difficult to find a

selective inhibitor for kinases

• Gleevec binds to the inactive form,

which is structurally different in the

various kinases, and thereby achieves

good selectivity

Gleevec binds to the inactive conformation of

BCR-ABL


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Gleevec: Pharmacological Profiling

• In-vitro studies

– The selective inhibitory activity of Gleevec was demonstratedon a cellular level on the constitutively active p210(BCR-ABL)

kinase.

– Inhibition of autophosphorylation of BCR-ABL by Gleevec

• In-vivo studies

– treatment of BCR-ABL transformed cell-lines with Gleevec

results in dose-dependent reduction of tumor growth

– the anti-tumor effect is specific for BCR-ABL expressing cells

– Gleevec re-activates apoptosis in BCR-ABL cells by suppressing

the capacity of STAT5 to activate the expression of the anti-apototic protein BCL-XL.

– Gleevec restores normal cell-cycle progression


Gl : Cli i l D l t


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Gleevec: Clinical Development

• Demonstration of dose-response relationship in patients with

chronic phase CML.

• mathematical modelling of data confirmed the useful therapeutic

dose to be around 400mg• a large multinational study with close to 1000 patients from all

three phases of the disease revealed that treatment was most

efficient when started in an early phase of disease progression

• approval by FDA in 2001

• efficiency of Gleevec can be improved by co-administration of

inhibitors of P-glycoprotein

• studies of factors leading to Gleevec resistance

Chronic phase

Median 4–6 years stabilization

Accelerated phase

Advanced phases

Median duration upto 1 year

Blastic phase (blast crisis)

Median survival3–6 months


F f D l


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Time-Frame for Development



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Fighting resistances arising from Gleevec

• resistances occur upon selective pressure for forming mutations

that do not bind any more to Gleevec

• a non-competitive inhibitor may suppress formation of drug-

resistant BCR-ABL mutants because resistant strains need to

develop mutations in two unrelated regions of the proteinsimultaneously

• a allosteric inhibitor was developed that binds to the myristate

binding site of the BCR-ABL kinase (GNF-2/GNF-5)

• combination therapy with Gleevec and GNF-2 seems to completely

suppress formation of resistant forms of BCR-ABL kinase

Zhang et al., Nature 2010 (463), 501.

D l t f ll t i i hibit f BCR ABL


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Development of allosteric inhibitors of BCR-ABL

122.0

125.0

124.0

123.0

122.0

125.0

124.0

123.0

8.0 7.0 p.p.m. 7.0 p.p.m.8.0

ATP binding site

myristyl binding site


combinations are more resistant


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combinations are more resistant

towards resistance

25 10 5 4 2 1 25 10 5

Day 9

Day 12

Day 210

8491

2 1070

9691

0

7581

2 440

96

72

0

52 59

2 200

96

66

0

50

100

SH3 domainSH3 domain

S229PS229P

P112SP112S

Y128DY128D

SH2 domainSH2 domain

F497LF497L

E505K E505K

COOHCOOH

V506LV506LC464YC464Y

T315l T315l

Y139CY139C

P465SP465S

MyristoylpocketMyristoylpocket

Catalytic siteCatalytic site

Kinase domainKinase domain

H2NH2N

GNF-2 Imatinib GNF-2 + 1 µM imatinib

Concentration (µM)

R e s i s t a

n t c o

l o n i e s

Mutations indicated by red spheres on Abl

with size proportional to the degree of resistance

Effect of various concentrations of GNF-2, imatinib, or combinations of both on the number of emerging Ba/F3.Bcr–Abl-resistant clones


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