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
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ADME (adsorption, distribution, metabolism and excretion) of drugs
drug-receptor interactions
development of drugs
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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
of the mother
2 infection of appendix
3 accidents
3
quality of
life
2
1
age
Medicine ca. 1950
1 childbed fever
of the mother
asepsis
2 infection of the appendix
3 accident → tetanus
vaccination
3
quality of
life
2
1
age
anesthesia,
antibiotics
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
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 2002–2004
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
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)
GSK
small molecule
$8.3 billion
4
Remicade (infliximab)
Asthma, chronic
obstructive
pulmonary disease
Rheumatoid
arthritis
Johnson &
Johnson/Janssen
antibody
$8.3 billion
5
Rituxan (rituximab)
Roche/Genentech
antibody
$8 billion
6
Lantus (insulin glargine)
Lymphoma,
leukemia and
rheumatoid
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
HO
O
(CH 2 ) 6
H 3C
(CH 2 ) 4
Salmeterol
H 3C
HO
S
N
N
HO
O
O
N
H
CH 3
N
CH 3
HO 2 C
F
N
Cl
Rosuvastatin
O
H 3C
CH 3
C
N
N
N
H
N
H
N
N
F
H
Budesonide
Aripiprazole
NH 2 O
OH
Sitagliptin
CH 3
CH 3 O
N
N
F
O
H
N
H
N
Imatinib mesylate
H
CH 3
O
F
N
CH 2
O
O
N
Cl
OH
(CH 2 ) 4
O
H
H 3C
H
N
O
H
O
H
O
OH
N
NH
OHC
Formoterol
CF 3
CH 3 NH
S
O
O
S
F 3C
N
NH 2
O
N
CH 3
HO 2 C
CH 2
N
NH 2
Duloxetine
N
N
N
N
O
N
N
N
Telmisartan
Celecoxib
O
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
O
O
H
N
N
O
Lenalidomide
N
S
HO
S
CH 3 O
O
Br -
O
+
N CH 3
CH 3
O
Tiotropium bromide
CH 3
N
S
OCH 3
CH 3
N
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)
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)
1
2
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
O
OH
N
H
Cl
OH
N
F
HN
COOH
N
N
Ciprofloxacin
HO H
OH
H
N
N
OH
N
Gefitinib
NH2
H H
O
O
NH
N
O
Atorvastatin
O
O
O
F
N
N
COOH
F
N
NH
O
N
S
N
COOH
O
HN
NH
Indinavir
N
HO O
S
Imipenem
Lamivudine
O
F
O
O
N
O
N
O
H
CH3
N
H
N
N
O
S
O O
S
N
NH
O
H3C
N
HN
Linezolid
Rosiglitazone
N
N
O
O
Sildenafil
CH3
N
Blockbusters are often similar....
HO
OChiral
N
HO
O
O
DDT Vol. 7, No. 10 May 2002
Cl
N N
N
O
N
NH
H
N
O
S
Me
Lovastatin
O
N
N
Losartan
O Me
Omeprazole
HO
OChiral
O
O
N
O
O
H
N
N
H
N
NH
N
S
N
O
F
O
N
F
F
HO
Lansoprazole
O
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)
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
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 4–6 years stabilization
Median duration up
to 1 year
Blastic phase (blast crisis)
Median survival
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 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
0
25
P112S T315l
H 2N
0
10
0
2
0
4
4
Day 12
0
2
0
0
2
Day 9
10
GNF-2
2
59
52
5
66
Catalytic site
96
7
0
Kinase domain
SH3 domain
S229P
100
50
96
Day 21
Y128D
4
2
1
25 10
5
Imatinib
GNF-2 + 1 µM imatinib
Concentration (µM)
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.Bcr–Abl-resistant clones
Zhang et al., Nature 2010 (463), 501.