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 sources

Monographs:

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

(very good introduction)

H.-J. Bhm, 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. Czak, L. Krti, 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

Society before 1800

1 childbed fever
of the mother

2 infection of appendix
3 accidents

3
quality of
life

age

Medicine ca. 1950

1 childbed fever
of the mother
asepsis

2 infection of the appendix

3 accident tetanus
vaccination

quality of
life

age

anesthesia,
antibiotics

Medicine after ~ 1950

quality of
life

age

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

65 years and older...

Male

Female

Cardiac Infarction

2,9%

Pneumonia

2,8%

Pancreatic Cancer

3,0%

3,7%

Stroke

Stroke

3,5%

3,8%

Prostate Cancer

Cardiac Infarction

4,3%

4,7%

obstructive lung disease

(smokers lung)

Cardiac insufficiency
6,1%

6,9%

Cardiac insufficiency

Colon Cancer

8,3%

7,7%

Lung Cancer

Arteriosclerosis

9,8%

9,7%

Arteriosclerosis

2,7%

2,4%
1,7%

2008

hypertension-related
heart condition
Breast cancer
Pneumonia

2,3%

Cardiac arrhythmia

2,1%

Lung Cancer

2,1%

obstructive lung disease

(smokers lung)

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"

osa

Bacteria under the electron microscope

Escherichia Coli

Cholera

Stapphylococcus Aureus

Pseudomonas Aeruginosa

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?

Complexity

History of drug development

focus on
molecular function
accidential
observation

focus on
cell-biology

focus on
biochemistry

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

Blockbuster (2004)
Best-selling pharmaceutical products 20022004
Product

Company

Trade (Generic) name

Sales figures for 2002

(US$ billion)
Company

IMS

Sales figures for 2003

(US$ billion)
Company

Sales figures for 2004

(US$ billion)

IMS

Company

IMS

Lipitor (Atorvastatin)

Pfizer

cholesterol-lowering
8.60 medication
9.23
7.90

10.3

10.86

12.00

Zocor (Simvastatin)

Merck

5.60
agent
lipid-lowering6.20

5.01

6.10

5.20

5.90

Plavix (Clopidrogrel)

anti-platelet medication
BMS and Sanofi-Aventis 3.10
NA

4.20

3.70

5.20

5.00

Advair (Fluticasone; Salmetrol)

GSK

2.00
NA
anti-asthma medication

3.60

NA

4.50

4.70

Norvasc (Amlodipine)

Pfizer

agent
3.80
4.00
4.33
blood pressure-lowering

4.50

4.46

4.80

Zyprexa (Olanzapine)

Eli-Lilly

3.60
4.00
anti-depressant

4.27

4.80

4.42

4.80

Paxil (Paroxetine)

GSK

1.90
NA
anti-depressant

3.00

3.90

3.90

3.90

Nexium (Esomaprazole)

AstraZeneca

1.97
3.30produced in the
3.80stomach 3.88
decreases theNAamount of acid

4.80

Zoloft (Sertraline)

Pfizer

2.74
NA
anti-depressant

3.10

3.40

3.36

NA

Celebrex (Celecoxib)

Pfizer

3.00
NA drug
anti-inflammatory

1.90

2.50

3.30

NA

Effexor (Venlafaxine)

Wyeth

2.00
NA
anti-depressant

2.70

NA

3.30

3.70

Prevacid (Lansoprazole)

Takeda and Abbott

3.10

3.80

Diovan (Valsartan)

Novartis

3.10

NA

Fosamax (Alendronate)

Merck

3.10

NA

Risperdal (Risperidone)

J&J

3.30produced in the
4.00stomach
decreases the3.60
amount of acid
3.70
1.66
NA
2.50
NA
prevents vasoconstriction
NA agent 2.50
NA
anti-osteoporosis
2.20
2.10
NA
medication 2.50
antipsychoticNA

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.

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

name

disease area

company

drug class

sales 2013

Humira (adalimumab)

Rheumatoid
arthritis

AbbVie

antibody

$11 billion

Enbrel (etanercept)

Rheumatoid
arthritis

Amgen

recombinant
fusion protein

$8.75 billion

Advair (fluticasone
propionate and salmeterol)

GSK

small molecule

$8.3 billion

Remicade (infliximab)

Asthma, chronic
obstructive
pulmonary disease
Rheumatoid
arthritis

Johnson &
Johnson/Janssen

antibody

$8.3 billion

Rituxan (rituximab)

Roche/Genentech

antibody

$8 billion

Lantus (insulin glargine)

Lymphoma,
leukemia and
rheumatoid
Diabetes

Sanofi

insulin analogue

$7.5 billion

Avastin (bevacizumab)

Cancer

Roche

antibody

$6.5 billion

Herceptin (trastuzumab)

Cancer

Roche/Genentech

antibody

$6.5 billion

Crestor (rosuvastatin)

high cholesterol

AstraZeneca

small molecule

$6 billion

10

Januvia (sitagliptin)

diabetes

Merck

small molecule

$6 billion

Top small molecule drugs

OH
HO

(CH 2 ) 6

H 3C

(CH 2 ) 4

Salmeterol

H 3C
HO

HO

N
H

CH 3

CH 3

HO 2 C

N
Cl

Rosuvastatin
O
H 3C

CH 3

N
N

N
H

N
H

N
N

Budesonide
Aripiprazole

NH 2 O

OH

Sitagliptin

CH 3

CH 3 O

N
N

N
H

Imatinib mesylate

CH 3

CH 2

Cl

OH

(CH 2 ) 4

H 3C

H
N

H
O

H
O

OH

NH

OHC

Formoterol

CF 3

CH 3 NH
S

O
S
F 3C

NH 2

CH 3

HO 2 C

CH 2
N

NH 2

Duloxetine

Telmisartan

Celecoxib

NH 2

CH 3
H 3C

NH 2
CO 2 H

Pregabalin

Tenofovir

CH 3

CH 3

PO 3 H 2

CH 3

H
N

H
N

N
O

Lenalidomide

S
HO
S

CH 3 O

O
Br -

N CH 3
CH 3

Tiotropium bromide

CH 3

OCH 3
CH 3

N
N N
H
O

Esomeprazole

N
HO 2 C

CH 3
CH 3

Valsartan

predicted blockbusters (sales started/start soon)

Drug

Company

Revenue (Billion $)

Opdivo

Bristol-Myers
Squibb

$5.684

melanoma (antibody)

Praluent

Regeneron/
Sanofi Sanofi

$4.414

cholesterol lowerer (antibody)

LCZ-696

Novartis

$3.731

angiotensin receptor-neprilysin
inhibitor (small molecule)

Ibrance

Pfizer

$2.756

breast cancer (small molecule)

Iumacaftor

Vertex

$2.737

cystis fibrosis (small molecule)

Viekira Pak

AbbieVie

$2.500

antiviral cocktail (small molecule)

Evolocumab

Amgen/
Astellas

$1.862

cholesterol lowerer (antibody)

Gardasil 9

Merck & Co.

$1.637

cancer vaccine for young women

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)

1
2

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

Properties of typical drugs

small, organic molecules (Lipinskis 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
O

OH

N
H

Cl

OH

HN

COOH

Ciprofloxacin

HO H
OH

H
N

OH

Gefitinib

NH2
H H

NH

Atorvastatin

COOH

NH

N
S

COOH

HN
NH

Indinavir

HO O

Imipenem

Lamivudine

O
N

O
H

CH3
N

H
N

O O
S
N

NH
O
H3C

HN

Linezolid

Rosiglitazone

N
N

Sildenafil

CH3
N

Blockbusters are often similar....

HO

OChiral

HO

DDT Vol. 7, No. 10 May 2002

Cl

N N
N

NH
H
N

O
S

Me

Lovastatin

Losartan
O Me

Omeprazole
HO

OChiral
O

N
O

H
N
NH

F
O

F
F

HO

Lansoprazole

Simvastatin

Valsartan
Drug Discovery Today

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).

Recombinant Drugs
SUPPLEMENTARY INFORMATION

In format provided by Goodman (NOVEMBER 2009)

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

Product

Company

2013E consensus
revenue (billions)

2012E2013E
% 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

Gleevec binds to the inactive conformation of

BCR-ABL

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: 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 antiapototic protein BCL-XL.
Gleevec restores normal cell-cycle progression
Capdeville, Nat.Rev.Drug.Discov. 1 (2002),493

Gleevec: Clinical Development

Chronic phase

Advanced phases
Accelerated phase

Median 46 years stabilization

Median duration up
to 1 year

Blastic phase (blast crisis)

Median survival
36 months

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

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

Time-Frame for Development

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 drugresistant 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

122.0

123.0

123.0

124.0

124.0

125.0

8.0

7.0 p.p.m.

125.0

8.0

7.0 p.p.m.

ATP binding!
site

myristyl binding!
site

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

combinations are more resistant

towards resistance
Mutations indicated by red spheres on Abl
with size proportional to the degree of resistance

84
75

91

91

96

81

72

Resi
stan
t col

onie
s

25

P112S T315l
H 2N

10

Day 12

Day 9

10
GNF-2

59

52

66

Catalytic site

96
7

Kinase domain

SH3 domain
S229P

100

50

96

Day 21
Y128D

2
1
25 10
5
Imatinib
GNF-2 + 1 M imatinib
Concentration (M)

SH2 domain

Y139C
C464Y
V506L
F497L
E505K

P465S
Myristoyl
pocket
COOH

Effect of various concentrations of GNF-2, imatinib, or combinations

of both on the number of emerging Ba/F3.BcrAbl-resistant clones

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