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. 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
 Society before 1800
1 childbed fever 2 infection of appendix
of the mother

3 accidents

quality of 2
life

age
 Medicine ca. 1950
anesthesia,
1 childbed fever 2 infection of the appendix
antibiotics
of the mother

asepsis 3 accident → tetanus

vaccination
3

quality of 2
life

age
 Medicine after ~ 1950

quality of
life

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

8
 65 years and older...
Male Female

Arteriosclerosis 9,7% 9,8% Arteriosclerosis

Cardiac Infarction 7,7% 8,3% Cardiac insufficiency

Lung Cancer
6,9% 6,1% Cardiac Infarction

Cardiac insufficiency 4,7% 4,3% Stroke

obstructive lung disease 3,8% 3,5% hypertension-related

(smokers lung) heart condition
Prostate Cancer
3,7% 3,0% Breast cancer

Stroke 2,9% 2,7% Pneumonia

Pneumonia 2,8% 2,3% Cardiac arrhythmia

Colon Cancer
2,4% 2,1% Lung Cancer

Pancreatic Cancer obstructive lung disease

1,7% 2,1%
(smokers lung)

2008
 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"
 Bacteria under the electron microscope
Escherichia Coli Stapphylococcus Aureus

osa Cholera 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?

 History of drug development

focus on
Complexity

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 2002–2004
Product Company Sales figures for 2002 Sales figures for 2003 Sales figures for 2004
Trade (Generic) name (US$ billion) (US$ billion) (US$ billion)
Company IMS Company IMS Company IMS
Lipitor (Atorvastatin) Pfizer •7.90 8.60 medication
cholesterol-lowering 9.23 10.3 10.86 12.00
Zocor (Simvastatin) Merck • lipid-lowering6.20
5.60 agent 5.01 6.10 5.20 5.90
Plavix (Clopidrogrel) BMS and Sanofi-Aventis •3.10 NA
anti-platelet medication 4.20 3.70 5.20 5.00
Advair (Fluticasone; Salmetrol) GSK • anti-asthma medication
2.00 NA 3.60 NA 4.50 4.70
Norvasc (Amlodipine) Pfizer • blood pressure-lowering
3.80 4.00 4.33
agent 4.50 4.46 4.80
Zyprexa (Olanzapine) Eli-Lilly • anti-depressant
3.60 4.00 4.27 4.80 4.42 4.80
Paxil (Paroxetine) GSK • anti-depressant
1.90 NA 3.00 3.90 3.90 3.90
Nexium (Esomaprazole) AstraZeneca • decreases theNAamount of acid
1.97 3.30produced in the
3.80stomach 3.88 4.80
Zoloft (Sertraline) Pfizer • anti-depressant
2.74 NA 3.10 3.40 3.36 NA
Celebrex (Celecoxib) Pfizer • anti-inflammatory
3.00 NA drug 1.90 2.50 3.30 NA
Effexor (Venlafaxine) Wyeth • anti-depressant
2.00 NA 2.70 NA 3.30 3.70
Prevacid (Lansoprazole) Takeda and Abbott •3.70
decreases the3.60 3.30produced in the
amount of acid 4.00stomach 3.10 3.80
Diovan (Valsartan) Novartis • prevents vasoconstriction
1.66 NA 2.50 NA 3.10 NA
Fosamax (Alendronate) Merck •2.20 NA agent 2.50
anti-osteoporosis NA 3.10 NA
Risperdal (Risperidone) J&J • antipsychoticNA
2.10 medication 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.
 Blockbusters 2013 (C&N news, supl. 09/14)
name disease area company drug class sales 2013

1 Humira (adalimumab) Rheumatoid AbbVie antibody $11 billion

arthritis
2 Enbrel (etanercept) Rheumatoid Amgen recombinant $8.75 billion
arthritis fusion protein
3 Advair (fluticasone Asthma, chronic GSK small molecule $8.3 billion

propionate and salmeterol) obstructive
pulmonary disease
4 Remicade (infliximab) Rheumatoid Johnson & antibody $8.3 billion
arthritis Johnson/Janssen
5 Rituxan (rituximab) Lymphoma, Roche/Genentech antibody $8 billion
leukemia and
rheumatoid
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
OH O O
N H 3C S
H O CH 3 O
HO (CH 2 ) 6 (CH 2 ) 4 N H
H O O
O H
HO N N
H 3C H CH 3
O
Salmeterol H 3C H
N O
CH 3 (CH 2 ) 4 H H
HO F O
N O
HO 2 C
N
OH Cl Budesonide
Cl
Rosuvastatin Aripiprazole

O CH 3 OH
N N
H 3C C F H
N N N N
H H F NH 2 O
N CH 3
CH 2 N CH 3 O OH
N N
NH
N OHC
Imatinib mesylate F N
CF 3 Formoterol
Sitagliptin CH 3 NH
S
O

S NH 2 NH 2
CH 3
N O
HO 2 C
CH 2 N
Duloxetine N
N N O
F 3C N PO 3 H 2
N N N
CH 3
N

CH 3 CH 3 Tenofovir
Celecoxib Telmisartan

O H
N O CH 3
NH 2 N N
O H
N S N
N OCH 3
NH 2 N N
H
CH 3 S N CH 3
O
CO 2 H HO O
H 3C S O CH 3 O
Lenalidomide +
N CH 3 Esomeprazole N
O CH 3
Pregabalin Br - CH 3
O HO 2 C
CH 3
Tiotropium bromide Valsartan
predicted blockbusters (sales started/start soon)
Drug Company Revenue (Billion $)

1 Opdivo Bristol-Myers $ 5.684 melanoma (antibody)

Squibb
2

2 Praluent Regeneron/ $ 4.414 cholesterol lowerer (antibody)

Sanofi Sanofi
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/ $ 1.862 cholesterol lowerer (antibody)

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

9 Brexpiprazole Ostuka/ $ 1.353 schizonphrenia/depression (small

Lundbeck 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
Cl
O OH OH
HN F
COOH
N N N N
H
O NH

F COOH N O
N
O
F O N

Atorvastatin Ciprofloxacin Gefitinib

NH2
HO H
N OH H H
H OH N
N N S
N N HO O N
O O
O NH COOH HN O
NH
S

Indinavir Imipenem Lamivudine

O
O O
N CH3
O N
CH3 O O HN
NH N
F N N N S S
O N N
H O
N O N
H H3C O
O

Linezolid Rosiglitazone Sildenafil

 Blockbusters are often similar....
HO OChiral Cl DDT Vol. 7, No. 10 May 2002
N
O HO
O
N N N
O N NH

H
N O
S N
Me N
O
Lovastatin
Losartan
Omeprazole O Me

HO OChiral
H
O N N
O N S
N NH
N O
O F F
O N
H
N O F
HO
O 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 2012E–2013E

revenue (billions) % 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 anti-
apototic 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 Blastic phase (blast crisis)

Median duration up Median survival

Median 4–6 years stabilization
to 1 year 3–6 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 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

122.0 122.0

123.0 123.0

124.0 124.0

125.0 125.0
8.0 7.0 p.p.m. 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

Kinase domain
91 91 96 SH3 domain
84 S229P
96
81 P112S T315l Catalytic site
75 72
96
100 H 2N
66 7 10
Resi

0 2 0 Day 21
52 59
Y128D
stan

2 4 4 Y139C
50 0 0 Day 12 SH2 domain
t col

0 2 0 0 2 Day 9 C464Y
onie

V506L
0 F497L
P465S
25 10 5 4 2 1 25 10 5
s

Myristoyl
E505K pocket
GNF-2 Imatinib GNF-2 + 1 µM imatinib COOH
Concentration (µM)

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.