Những khám phá và phát triển của hoá dược

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.

Ex: Color Red / Bood () haemostatic derived from hibiscus).
Shape / Organ (crocus bulb for gout treatment, big toe).
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HISTORY IN BIEF
 1763: medicinal properties of extract of willow bark and leaves observed
Edward Stone (headache, stomachache, and other body pain).
 1829: Isolation of salicin by H. Leroux
 1853: Transformation from salicin to acetyl
salicylic
acid by Charles
Gerhardt.
 1899: Bayer’s market launch of Aspirine.
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HISTORY IN BRIEF
 From 19
th
century: DRUG = PURE COMPOUND.
9 1803: Isolation of morphine from opium poppy by Friedrich Serturner.
9 1819-1820: Isolation of strychnine, caffeine, quinine and colchicine by
Pelletier and Caventou

End
of 19
th
century – Beginning of 20
th
century:
9 “Lock - Key” (E. Fisher).
9 “Magic Bullet” (P. Ehrlich): structure – activity.
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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

PRECLINICAL PHASE (animal test)
 Exact knowledge of the molecule (pilot scale synthesis with purity > 99%
,
clearly identified impurities, stability within 6 month, available galenic form).
 Toxicity (acute, chronic, sub-chronic (5-
90
days)).
 Evaluation of mutagenic risk.
 Studying of effects on reproduction (fertility, embryo, death and postnatality)
.
Assurance of security in the test on human
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DRUG DISCOVERY AND DEVELOPMENT
CLINICAL PHASE I
 The first administration to human (~ 1 year with > 100-200 volunteers → 5-
30
kg).
 Studying clinical and biological tolerance on human.
 Determination of maximum tolerated
dose
(1
st
administrated dose = 1/
10
maximum dose without unacceptable toxicity on animal).
 Verification of pharmacokinetic properties .
CLINICAL PHASE IIa: verification of therapeutic effects and side effects in
short
term.
End of development research: molecule = medication ?

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.

 Supplementary protection certificate (SPC).
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DRUG DEFINITION
 Drug: at molecular scale, drug means a substance being able to interact with a
biological
system in order to give a biological response.
 Official definition of Drug: a drug is a chemical substance which may have
medicinal,
intoxicating, performance enhancing or other effects when taken or put into a human
body
or the body of another animal and is used in the treatment, cure, prevention, or
diagnosis
of disease or used to otherwise enhance physical or mental well-
being
.
 Drug = active ingredient + excipient.
 Excipient:
9 Carrier for active ingredients.
9 Stabilize the active ingredient.
9 Antiadherents (magnesium stearate), Binders(saccharide, protein, polymer).
9 Disintegrants.
9 Fillers (lactose, sucrose, glucose, mannitol, sorbitol).
9 Flavours, Colors , Preservatives , Sweeteners.
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DRUG DISCOVERY
Source of Drugs
→ 52% drugs from
nature or nature-inspired.
Atorvastatine (Lipitor): best-seller drugs – 11 billions USD in 2004.
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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

R=H adrenaline
R=Me noradrenaline
Increased size
(selectivity and duration)
Catechol
bioisostere
(toxicity)
Increased size
(selectivity and duration)
NH
OH
OH
N
H
O
O
H
Formoterol
AstraZeneca
OH
OH
N
H
OH
Salbutamol
GlaxoSmithKline
Catechol
bioisostere
(toxicity)
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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

S
N
O O
N
Levitra
(Vardenafil)
Bayer
Issues: short duration
Multiple side effects and
incompatibility with other drugs
NH
N
N
N
O
O
S
N
O O
N
Viagra
Pfizer
Fewer side effects and
incompatibility with other drugs
36h duration (“the weekend pill”)
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DRUG DISCOVERY
Synthetic molecules
 Inspiration from side effects of existent drugs
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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

• HTS assay technologies
and automation
• chemical diversity
• sample selection for HTS
How?
“An industrialised process which brings together validated,
tractable targets and chemical diversity to rapidly identify
novel lead compounds for early phase drug discovery”
50-70% of new drug projects originate from a HTS
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DRUG DISCOVERY
High-throughput screening (HTS)
OH
N
Cl
O
O
chemical
space
compound
collection
compound
selection
human & pathogen
genomes
validated/
tractable
targets
target
ID

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

g
g
g
g
g
g
g
g
g
g
g


S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S

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

y
y
y
y
y
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n

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

h
h
h
h
h
h
h
h
h
h
h
h
h
h
h
e
e
e
e
e
e
e
e
e
e
e
e
si
s
 Combinational Synthesis

 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:

9 Activity.
9 Selectivity.
9 Accessibility.
9 Stability.
9 Toxicity.
9 Bioavailability.
 Studying on pharmacodynamics
9 Structue – Activity relationship (SAR)
.
9 Identification of pharmacophore.
9 Optimization of drug – target interaction.
 Studying on pharmacokinetics
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LEAD OPTIMIZATION
Structure – Activity relationship
9 Identifying the functional group giving activity.
9 Method: transforming, removing or masking each group.
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LEAD OPTIMIATION
 Alcohol - Phenol
Structure – Activity relationship
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LEAD OPTIMIZATION
 Alkene - Arene
Structure – Activity relationship
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LEAD OPTIMIZATION
 Role of carbonyl group
Structure – Activity relationship
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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

 Rigidification of lead molecule: to 'lock' the drug molecule into a more
rigid
conformation such that it cannot take up these other shapes or
conformations
(hence other receptor interactions and side-effects are eliminated).
Pharmacodynamics
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LEAD OPTIMIZATION
 Rigidification of lead molecule
Pharmacodynamics
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LEAD OPTIMIZATION
 Drug design for pharmacodynamic problems
9 Extension of the structure.
9 Ring extensions/contractions.
9 Chain extensions/contractions.
Pharmacodynamics
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LEAD OPTIMIZATION
 Drug design for pharmacodynamic problems
9 Ring variations.
Pharmacodynamics
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LEAD OPTIMIZATION
 Drug design for pharmacodynamic problems
9 Variation of substituents.
Pharmacodynamics
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