REFERENCES
 G. L. Patrick, An introduction to medicinal chemistry, Oxford university
press 2005
 Anthony J. Hickey, David Ganderton, Pharmaceutical Process
Engineering, Informa Healthcare USA, Inc 2010.
 Bianca Piachaud,
Outsourcing
R&D in the Pharmaceutical Industry
,
Bianca Piachaud 2004.
 Bill Bennett, Graham Cole, Pharmaceutical production – An engineering
guide, Chemical Engineers (IChemE) 2003.
 Michael Levin, Pharmaceutical Process Scale-up, Marcel Dekker, Inc
2002.
 David G. Watson,
Pharmaceutical
Analysis, Harcourt Publishers 1999.
 Gary Walsh, Brendan Murphy, Biopharmaceuticals - An
industrial
perspective, Kluwer Academic Publishers 1999.
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HISTORY IN BRIEF
 Primitive traces of medicinal chemistry:
9 Clay tablets (2600 BC, Sumérie): 1000 plants.
9 Ebers Papyrus (1500 BC, Egypt): 800 preparations.
9 Hippocrates (440-377 BC).

…
until 19th century: preponderance of plant-based potion.
9 Empiricism and theory of signature: similarity in characteristics of plants
and the organ.

DRUG DISCOVERY AND DEVELOPMENT
DISCOVERY PHASE
 Choice of malady (medical demands, economic factors , strategy of
lab,
concurence).
 Choice of therapeutic target (mechanism, pertinence, distribution,
selectivity,
cells).
 Choice of biological test (in vitro, in vivo, method of screening, number
of
compounds).
 Screening and selection of lead (isolation, structure, patent).
 Elimination of molecules being difficult to project (complex
structure,
stability, toxicity).
Lead substances
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DRUG DISCOVERY AND DEVELOPMENT
OPTIMIZATION PHASE
 Studying of Structure – Activity Relationships (SAR).
 Identificaiton of pharmacophore
 Optimization of pharmacodynamic properties.
 Optimization of pharmacokinetic properties and solubility.
The best molecule (less toxic, in-vivo active, formulable)
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DRUG DISCOVERY AND DEVELOPMENT
OPTIMIZATION PHASE
M. McCoss, Organic chemistry in drug discovery, T. A. Baillie Science 2004, 303, 1810
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DRUG DISCOVERY AND DEVELOPMENT

Beginning of industrial development: molecule

medication.
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DRUG DISCOVERY AND DEVELOPMENT
CLINICAL PHASE IIb
 Determination of effective therapeutic dose, dosage and type
of
administration (~ 2 years on 20-80 volunteers → 30-100 kg).
 Double blind test / placebo or existing medications (cancer or AIDS).
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DRUG DISCOVERY AND DEVELOPMENT
CLINICAL PHASE III (~ 3 years, 50-300 kg)
 Demonstration of surety and effectiveness of novel medication
(larger
population of patients).
 Comparison with drugs already on the market.
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DRUG DISCOVERY AND DEVELOPMENT
INTERNATIONAL REGISTRATION
 Favorable ratio of Benefits – Risks.
 Impeccable pharmaceutical quality.
 Safety methods in preclinical and clinical trials.
 Clinical effectiveness proved in claimed indication.
PHARMACOVIGILANCE (CLINICAL PHASE IV)
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DRUG DISCOVERY AND DEVELOPMENT
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DRUG DISCOVERY AND DEVELOPMENT
 20 years patented.

DRUG DISCOVERY
Natural molecules
M. S. Butler, Nat. Prod. Rep. 2005, 22, 1620.
Frogs Fishes Snakes
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DRUG DISCOVERY
Natural molecules
M. S. Butler, Nat. Prod. Rep. 2005, 22, 1620.
Plants (300.000 – 400.000 species, 10% investigated)
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DRUG DISCOVERY
Natural molecules
M. S. Butler, Nat. Prod. Rep. 2005, 22, 1620.
Bacteria, fungus
(> 1.000.000 species, but <10% bacteria , 5% fungus investigated)
Marine sources: algae, corals, sponges (500. 000 species, less-investigated)
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DRUG DISCOVERY
Nature-inspired molecules
 Inspiration from receptor’s natural ligand
 Inspiration from enzyme’s natural substrate
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DRUG DISCOVERY
Nature-inspired molecules
OH
OH
OH
N
H
R

DRUG DISCOVERY
Synthetic molecules
 Inspiration from (“mee too” drugs)
9 Economic and competitive aspects.
9 Lower risk: guaranteed activity and validated biologic tests.
9 Improvement of pharmacological profile: activity, selectivity, toxicity …
 Test
of
intermediate molecules of the synthesis route: structure relating to
target
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DRUG DISCOVERY
Synthetic molecules
N
O
O
N
N
H
O
O
Cialis
(Tadalafil)
Eli Lilly
NH
N
N
N
O
O

DRUG DISCOVERY
Synthetic molecules
 Chance or serendipity
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DRUG DISCOVERY
High-throughput screening (HTS)
Target
Identification
HTS
Hit-to-Lead
(HtL)
New Lead
Optimisation
Projects (LO)
Candidate
Drug (CD)
Active-to-Hit
(AtH)
3 months to
2 years!
3-4 months
3 months
6-9 months
2 years
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DRUG DISCOVERY
High-throughput screening (HTS)
• validated, tractable targets
• target selection for HTS
• industrialised process

HT Screen
Development
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DRUG DISCOVERY
Drug SynthesisDr
u
u
u
u
u
u
u
g
g
g
g
g
g
g
g
g
g
g
g
g
g
g
g
g
g

S
S
S
S
S
S
S
S
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y
y

t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
t
h
h
h
h
h
h
h
h
h
h

 Diversity-Oriented Synthesis
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DRUG DISCOVERY
Drug Synthesis
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DRUG DISCOVERY
Drug Synthesis
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DRUG DISCOVERY
DOS
D. S. Tan, Curr. Opin. Chem. Biol. 2005, 9, 248.
~ 2500 compounds
M. D. Shair, J. Am. Chem. Soc. 2001, 123, 6740.
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DRUG DISCOVERY
DOS
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DRUG DISCOVERY
Fragment-based lead discovery
 Combination of two fragment resulting activity.
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DRUG DISCOVERY
Fragment-based lead discovery
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DRUG DISCOVERY
Fragment-based lead discovery
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LEAD OPTIMIZATION
Objectives
 Optimization of the chosen molecule:

LEAD OPTIMIZATION
 Tertiary amine
Structure – Activity relationship
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LEAD OPTIMIZATION
 Isostere: to alter the character of the molecule in as subtle a way as possible.
Structure – Activity relationship
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LEAD OPTIMIZATION
Pharmacodynamics
 Identification of pharmacophore
9 Functional groups for target interaction.
9 Relative position of each functional groups.
9 Acvitve conformations.
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LEAD OPTIMIZATION
 Simplification of lead molecule
9 Discard non-essential parts of the structure without losing activity (typically
in
the case of natural compounds).
Excessive simplicity:
lost of activity /
selectivity due to lower
restriction of rotation.
9 Elimination of
asymmetric
centers.
Pharmacodynamics
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LEAD OPTIMIZATION