Medicinal Chemistry

all material is available online as pdf files under the following URL:

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

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.)

Books and other information sourcesMonographs:

• 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

age

quality of life

childbed fever of the mother

1

1 infection of appendix

2

2

3

accidents3

Society before 1800

1

1

2

2

3

3

Medicine ca. 1950

asepsis

anesthesia, antibiotics

vaccination

age

quality of life

childbed fever of the mother

infection of the appendix

accident → tetanus

Medicine after ~ 1950

age

quality of life

8

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

65 years and older...

2008

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

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

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 with cattle and had caught the cowpox disease (a mild disease related to smallpox) were immune and never caught smallpox. He inoculated a boy with blister fluid from a woman with cowpox. He later inoculated the same boy with fluid from smallpox, and discovered that the boy was immune against the disease.

• Bill Withering introduces extracts of Digitalis for treatment of heart problems

• Louis Pasteur discovers that microorganisms are responsible for diseases and develops vaccinations against rabies. He introduces attenuated viruses for treatment of rabies.

until 1900

• Digitalis (isolated from the plant digitalis, stimulation of

the 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

Discovery of Penicillin• Alexander Flemming discovers in 1928 that a fungus grew on a

bacterial plate containing staphylococci. Close to the fungus all bacteria were killed.

• Biotechnological production of penicillins was established during the second world war and helped saving the life of many soldiers

13

Robert Koch !Nobel laureate 1905 "for his discovery and treatment of tuberculosis"

Pseudomonas Aeruginosa

Bacteria under the electron microscopeEscherichia Coli

CholeraPseudomonas Aeruginosa

Stapphylococcus Aureus

Since then....

• Early 1900: synthetic drugs, foundation of pharmaceutical industry

• 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?

Com

plex

ity

accidential observation

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

Blockbuster (2004)Best-selling pharmaceutical products 2002–2004

Sales figures for 2002(US$ billion)

Sales figures for 2003(US$ billion)

Sales figures for 2004(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

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

name disease area company drug class sales 2013

1 Humira (adalimumab) Rheumatoid arthritis

AbbVie antibody $11 billion

2 Enbrel (etanercept) Rheumatoid arthritis

Amgen recombinant fusion protein

$8.75 billion

3 Advair (fluticasone propionate and salmeterol)

Asthma, chronic obstructive

pulmonary disease

GSK small molecule $8.3 billion

4 Remicade (infliximab) Rheumatoid arthritis

Johnson & Johnson/Janssen

antibody $8.3 billion

5 Rituxan (rituximab) Lymphoma, leukemia and rheumatoid

Roche/Genentech antibody $8 billion

6 Lantus (insulin glargine) Diabetes Sanofi insulin analogue $7.5 billion

7 Avastin (bevacizumab) Cancer Roche antibody $6.5 billion

8 Herceptin (trastuzumab) Cancer Roche/Genentech antibody $6.5 billion

9 Crestor (rosuvastatin) high cholesterol AstraZeneca small molecule $6 billion

10 Januvia (sitagliptin) diabetes Merck small molecule $6 billion

Top small molecule drugs

Salmeterol

(CH 2) 6 (CH 2) 4

HO

HO

OH

ONH

Rosuvastatin

CH 3

CH 3

H3C

H3C

HO2CHO

OH

N

F

N

O O

S

N

SitagliptinCF 3

NH 2 O

NN

NN

F

F

F

Imatinib mesylate

CH 2

H3C NN

C

O

NH

CH 3

N

N

NH

N

Aripiprazole

(CH 2) 4

ClCl

OO

HN

NN

Duloxetine

CH 3NH

OS

Pregabalin

CH 3

H3CCO 2H

NH 2

Lenalidomide

NH 2

HN

N

O

O

O

Tiotropium bromide

CH 3

CH 3O

O

S+N

Br -

S

OHO

Esomeprazole

OCH 3

CH 3

CH 3O

CH 3

S

N

N

HN

O

Valsartan

CH 3

CH 3

HO2C

N

N

NNH

N

O

Budesonide

H3C CH3

O

O

OO

HO

HO

H

HH

H

Formoterol

CH 3OCH 3

NH

OH

OH

OHCNH

Tenofovir

NH 2

CH 3

PO 3H2N

NN O

N

Celecoxib

NH 2

F3C

O

O

S

NN

CH 3

Telmisartan

N

N

N

N

CH 3HO2C

CH 3

CH 2

predicted blockbusters (sales started/start soon)Drug Company Revenue (Billion $)

1

2

Opdivo Bristol-Myers Squibb

$ 5.684 melanoma (antibody)

2 Praluent Regeneron/Sanofi Sanofi

$ 4.414 cholesterol lowerer (antibody)

3 LCZ-696 Novartis $ 3.731 angiotensin receptor-neprilysin inhibitor (small molecule)

4 Ibrance Pfizer $ 2.756 breast cancer (small molecule)

5 Iumacaftor Vertex $ 2.737 cystis fibrosis (small molecule)

6 Viekira Pak AbbieVie $ 2.500 antiviral cocktail (small molecule)

7 Evolocumab Amgen/ Astellas

$ 1.862 cholesterol lowerer (antibody)

8 Gardasil 9 Merck & Co. $ 1.637 cancer vaccine for young women

9 Brexpiprazole Ostuka/Lundbeck

$ 1.353 schizonphrenia/depression (small molecule)

10 Toujeo Sanofi $ 1.265 long-lasting insulin (protein)

11 Cosentyx Novartis $ 1.082 anti-inflammatory (antibody)

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

Properties of typical drugs

• small, organic molecules (Lipinski’s Rule of Five): molecularweight < 500, not too polar, not too many functional 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

Typical drugs

Indinavir

N

N

NHN

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

N OF

O

H

HN

O

NS

HN

NH

O

H H

COOH

HO H

Imipenem

N NO

SNH

O

O

CH3

Rosiglitazone

Atorvastatin

N

F

NH

OH OHO

COOH

gleevecgleevec

Blockbusters are often similar....

Figure 8. Structural similarity in blockbusters. Examples of structural similarities betweencompounds within a given class: 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductaseinhibitors (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

NHNN

NN

NCl

HO

LosartanO

Me N

HN

SO

N

O MeOmeprazole

OH

OO

HO OChiral

Simvastatin

NHN

NN

NO

OHO

ValsartanDrug Discovery Today

N

HN

SN

O

F

F

FO

Lansoprazole

Recombinant Drugs

SUPPLEMENTARY INFORMATION In format provided by Goodman (NOVEMBER 2009)

NATURE REVIEWS | DRUG DISCOVERY www.nature.com/reviews/drugdisc

Table S2 | Top five products by consensus revenue in 2013E

Product Company 2013E consensus revenue (billions)

2012E–2013E % change

Avastin Roche $8.90 6%

Advair Diskus GlaxoSmithKline $8.58 -10%

Humira Abbott $7.98 2%

Mabthera/Rituxan Roche $7.56 3%

Lantus Sanofi-Aventis $6.84 7%

Portfolio share of biologics

Derivates of Natural Products

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 9 and 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 the sole oncogenic event resulting in induction of Leukaemia in mice.

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

Gleevec: Medicinal Chemistry

• Lead compound identified from screen for inhibitors of the protein kinase C (PCK). Strong binding is retained when the pyridyl unit is added.

• Presence of an amide group on the phenyl ring provided inhibitory activity against tyrosine kinases such as BCR-ABL kinase (target hopping)

• Substitution at position 6 of the diaminophenyl ring abolished PCK inhibitory activity while retaining it at tyrosine kinases (increasing selectivity)

• Improvement of ADME properties. Addition of a polar side-chain markedly increases both solubility and oral bioavailability. To avoid the mutagenic potential of aniline compounds a CH2 spacer was inserted.

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

• 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

Gleevec: Pharmacological Profiling

• In-vitro studies

– The selective inhibitory activity of Gleevec was demonstrated on 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

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

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

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

Time-Frame for Development

June 1998 –First patient with CML treated.

1990 – Lead compound identified in a screen for inhibitors of PKC.

1996 – In vivo activity shown in BCR–ABL-transformedcells in syngeneic mice.

June 2000 –Phase III trials initiated.

November 2001 –Approved in Europe and Japan for CML.

May 2001 –Approved by the FDA for CML.

June 1999 –Phase II trials initiated.

1992 – First batch of Glivec synthesized.

February 2001 –NDA submittedto FDA for CML.

February 2002 –Approved by the FDA for GIST.

Discovery Clinical development

N

N

N N

H H

N

O

DiscoveryClinical

development

Typically ~8 years Typically ~7 years

Typical development timeline

Glivec development timeline

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

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 protein simultaneously

• 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.

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

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

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

E505KE505KCOOHCOOH

V506LV506LC464YC464Y

T315lT315l

Y139CY139C

P465SP465SMyristoylpocketMyristoylpocket

Catalytic siteCatalytic site

Kinase domainKinase domain

H2NH2N

GNF-2 Imatinib GNF-2 + 1 µM imatinibConcentration (µM)

Resistant colonies

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

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