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Medicinal Chemistry
all material is available online as pdf files
under the following URL:
http://www.oci.uzh.ch/group.pages/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
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classical medicinal chemistry, hit-to-lead development
combinatorial chemistry (D.O.)
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
computational chemistry in drug development (K.B.)
patent issues
Books and other information sources
Monographs:
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G. Patrick: Introduction to Medicinal Chemistry, Oxford University Press, 2005
(very good introduction)
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H.-J. Böhm, G. Klebe, H. Kubinyi: Wirkstoffdesign. Der Weg zum Arzneimittel
(Spektrum Lehrbuch) (very interesting, easy to read)
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G. Thomas: Medicinal Chemistry: An Introduction (Wiley), (inexpensive introduction)
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H. P. Rang, M. M. Dale, J. M. Ritter: Pharmacology, Churchill Livingstone; 6th ed.
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E.J. Corey, B. Czakó, L. Kürti, Molecules and Medicine (Wiley)
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D.S. Johnson, J.J. Li: The Art of Drug Synthesis (Wiley)
Journals:
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Nature Reviews Drug Discovery
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Drug Discovery Today
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ACS Journal of Medicinal Chemistry
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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)
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Egyptian medicine (3000 BC)
– Papyrus Ebers, 877 descriptions and recipies
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Greek medicine (from 700 BC)
– illness is no punishment from God, medicine is considered a science
– diseases are due to natural causes
– Hippocratic oath
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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 recipies
• Era of horrible epidemics (e.g. Pest, Lepra, Pox, Tuberculosis)
• Arabic medicine: Development of medical procedures for drug preparation
(destillation)
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
inocculated a boy with blister fluid from a woman with cowpox.
He later inocculated 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 froim 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"
nosa
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
Complexity
History of drug development
focus on
molecular function
accidential
observation
focus on
cell-biology
focus on
biochemistry
Blockbuster
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
cholesterol-lowering
8.60 medication
9.23
•7.90
IMS
Company
IMS
10.3
10.86
12.00
5.20
5.90
5.20
5.00
4.50
4.70
4.46
4.80
4.42
4.80
3.90
3.90
3.88
4.80
3.36
NA
Lipitor (Atorvastatin)
Pfizer
Zocor (Simvastatin)
Zoloft (Sertraline)
5.01
6.10
lipid-lowering6.20
agent
•5.60
anti-platelet medication
BMS and Sanofi-Aventis •3.10
NA
4.20
3.70
anti-asthma medication
GSK
NA
3.60
NA
•2.00
blood pressure-lowering
agent
Pfizer
4.00
4.33
4.50
•3.80
Eli-Lilly
4.00
4.27
4.80
anti-depressant
•3.60
anti-depressant
GSK
NA
3.00
3.90
•1.90
AstraZeneca
1.97
3.30produced in the
3.80stomach
• decreases theNAamount of acid
anti-depressant
Pfizer
NA
3.10
3.40
•2.74
Celebrex (Celecoxib)
Pfizer
Effexor (Venlafaxine)
Wyeth
Prevacid (Lansoprazole)
Takeda and Abbott
Diovan (Valsartan)
Novartis
Fosamax (Alendronate)
Merck
Risperdal (Risperidone)
J&J
Plavix (Clopidrogrel)
Advair (Fluticasone; Salmetrol)
Norvasc (Amlodipine)
Zyprexa (Olanzapine)
Paxil (Paroxetine)
Nexium (Esomaprazole)
Merck
NA drug
anti-inflammatory
•3.00
2.00
NA
• anti-depressant
Sales figures for 2004
(US$ billion)
1.90
2.50
3.30
NA
2.70
NA
3.30
3.70
3.10
3.80
3.10
NA
3.10
NA
3.00
NA
3.30produced in the
4.00stomach
decreases the3.60
amount of acid
•3.70
prevents vasoconstriction
NA
2.50
NA
•1.66
NA agent 2.50
NA
anti-osteoporosis
•2.20
antipsychoticNA
medication 2.50
NA
•2.10
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.
Properties of typical drugs
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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
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or: natural products
chemical synthesis should be not too complicated (price!)
no reactive groups in the molecule
Typcial 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
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Interferon
GM-CSF
EPO
Antibodies
Insulin
Factor VIII
3 Mrd. $
2,5 Mrd. $
3,5 Mrd. $
2,2 Mrd. $
2,9 Mrd. $
0,5 Mrd. $
Derivates of Natural Products
Gleevec: Target Identification
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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.
Gleevec binds to the inactive conformation of
BCR-ABL
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the structures of active kinases are
similar. Hence it is difficult to find a
selective inhibitor for kinases
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Gleevec binds to the inactive form,
which is structurally different in the
various kinases, and thereby achieves
good selectivity
Gleevec: Pharmacological Profiling
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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
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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
Gleevec: Clinical Development
Chronic phase
Advanced phases
Accelerated phase
Median 4–6 years stabilization
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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.
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mathematical modelling of data confirmed the useful therapeutic
dose to be around 400mg
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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
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approval by FDA in 2001
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efficiency of Gleevec can be improved by co-administration of
inhibitors of P-glycoprotein
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studies of factors leading to Gleevec resistance
Time-Frame for Development
Capdeville, Nat.Rev.Drug.Discov. 1 (2002),493