DRUG DISCOVERY AND

DEVELOPMENT
A drug may be broadly defined as any chemical
agent that affects living protoplasm.

EARLY EXPERIENCES WITH PLANTS

 The earliest drugs were discovered from
observation of the effects of plants after their
ingestion by animals.
 Valuable drugs were discovered with no
knowledge of their mechanism or site of action.
 For example goats gamboled and frisked through
the night after eating the berries of the coffee
plant.
 Mushrooms or the deadly nightshade plant were
used by professional poisoners.
 Belladonna was also used by the women to dilate
pupils (“beautiful lady”).
 Chinese herb ma huang (containing ephedrine) was
used over 5000 years as a circulatory stimulant.
 Curare containing arrow poisons were used for
centuries by South American Indians to paralyze and
kill animals.
 Poppy juice (opium) containing morphine was used
for pain relief and control of dysenteries.
 Many terrestrial and marine organisms remain
valuable sources of naturally occurring
compounds with various pharmacological
activities.

 Drug invention became more allied with the

advancement in synthetic organic chemistry and
revolution began in the dye industry.
 Dyes, by definition, are colored compounds with
selective affinity for biological tissues.

 Study of these interactions stimulated Paul

Ehrlich to postulate the existence of chemical
receptors in tissues that interacted with and
“fixed” the dyes.

 Similarly, Ehrlich thought that unique receptors

on microorganisms or parasites might react
specifically with certain dyes and that such
selectivity could spare normal tissue.
 Ehrlich’s work concluded in the invention of
arsphenamine in 1907, which was patented as
“salvarsan,” suggestive of the hope that the
chemical would be the salvation of humankind.

 This arsenic-containing compound and other

organic arsenicals were invaluable for the
chemotherapy of syphilis until the discovery of
penicillin.
 Gerhard Domagk discovered another dye,
prontosil (the first clinically useful sulfonamide),
that was shown to be dramatically effective in
treating streptococcal infections.

 The era of antimicrobial chemotherapy was born,

and the fascination with dyes soon spread to the
entire and nearly infinite spectrum of organic
chemicals.
The collaboration of pharmacology with chemistry, and
with clinical medicine has been a major contributor to the
effective treatment of disease, especially since the middle
of the 20th century.
 SOURCES OF DRUGS

 Diversity-oriented synthetic approaches are of obvious

value, while natural products (plant or marine animal
collections) are sources of novel and sometimes
exceedingly complex chemical structures.

 With the exception of a few naturally occurring

hormones such as insulin, most drugs were small organic
molecules until recombinant DNA technology permitted
synthesis of proteins by various organisms and
mammalian cells, starting in the 1980s.
 Insulin could be produced in great quantities by
purification from porcine or bovine pancreas obtained
from slaughter houses.

 Growth hormone, used to treat pituitary dwarfism, could

be used after purification from pituitary glands. The
danger of this approach was highlighted when patients
who had received the human hormone developed
Creutzfeldt-Jakob disease, a fatal degenerative
neurological disease caused by prion proteins that
contaminated the drug preparation.
 Gene cloning produce large quantities of proteins by
expressing the cloned gene in bacteria or eukaryotic cells
grown in enormous bioreactors.
 Macromolecules may also be used therapeutically. For
example, antisense oligonucleotides are used to block gene
transcription or translation, as these are small interfering
RNAs.
 Proteins utilized therapeutically include various hormones,
growth factors (e.g., erythropoietin, granulocyte-colony
stimulating factor), and cytokines, as well as a rapidly
increasing number of monoclonal antibodies now widely
used in the treatment of cancer and autoimmune diseases.
 Murine monoclonal antibodies can be
“humanized” (by substituting human for mouse
amino acid sequences).

 Alternatively, mice have now been “engineered”

by replacement of critical mouse genes with their
human equivalents, such that they make
completely human antibodies.
HITS TO LEADS
 Rarely any of the initial hits in a screen turn out
to be marketable drugs.
 Initial hits often have modest affinity for the
target, and lack the desired specificity and
pharmacological properties of a successful
pharmaceutical.
 Skilled medicinal chemists synthesize derivatives
of the hits, making substitutions at accessible
positions, and begin in this way to define the
relationship between chemical structure and
biological activity.
 Many parameters may require optimization,
including affinity for the target,
agonist/antagonist activity, permeability across
cell membranes, absorption and distribution in
the body, metabolism of the drug, and unwanted
effects.
 Modern drug development frequently determine
a high-resolution structure of the assumed drug
bound to its target.
 X-ray crystallography offers the most detailed
structural information.
 Using techniques of molecular modeling and
computational chemistry, the structure provides
the chemist with information about substitutions
likely to improve the “fit” of the drug with the
target and thus enhance the affinity of the drug
for its target

 Finally, we also will want to predict the

structural and functional consequences of a drug
binding to its target (a huge challenge), as well as
all relevant pharmacokinetic properties of the
molecules of interest.
TARGETS OF DRUG ACTION

 Modern drug invention usually start with certain protein or

pathway that plays a critical role in the pathogenesis of
disease, and altering that protein’s activity would therefore be
effective against perticular disease.
 Drugability refers to the ease with which the function of a
target can be altered in the desired fashion by a small organic
molecule.
 The drugability of a target with a low-molecular-weight
organic molecule relies on the affinity and selectivity of a
binding site with that molecule.
 If the target is an enzyme or a receptor for a small ligand, one
is encouraged. However, if the known ligands are large
peptides or proteins with an extensive set of contacts with
their receptor, the challenge is much greater.
 TARGET SELECTION & VALIDATION
 Define the unmet medical need (disease)
 Understand the molecular mechanism of the disease
 Identify a therapeutic target in that pathway (e.g gene, key enzyme,
receptor, ion-channel, nuclear receptor)
 Demonstrate that target is relevant to disease mechanism using
genetics, animal models, lead compounds, antibodies, RNAi, etc.

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DISCOVERY
 Develop an assay to evaluate activity of compounds on the target
- in vitro (e.g. enzyme assay)
- in vivo (animal model or pharmacodynamic assay)
 Identify a lead compound
 screen collection of compounds (“compound library”)
 compound from published literature
 screen Natural Products
 structure-based design (“rational drug design”)
 Mechanism-based design

 Optimize to give a “proof-of-concept” molecule—one that shows

efficacy in an animal disease model
 Optimize to give drug-like properties—pharmacokinetics,
metabolism, off-target activities
 Safety assessment, Preclinical Candidate!!!
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 Phase I Product Profile Marketing SOI
Investigational
10 - 100 healthy volunteers take
New Drug drug for about one month
application Information Learned

IND 1. Absorption and metabolism

2. Effects on organs and tissue
3. Side effects as dosage is increased

Remote data entry

Clinical
Phase II
Trials 50-500-impaired patients Information Learned
1. Effectiveness in treating disease
Treatment Group Control Group 2. Short-term side effects in health -impaired patients
3. Dose range

Phase III Information Learned

1. Benefit/risk relationship of drug
Hundreds or thousands of health- 2. Less common and longer term side effects
impaired patients 3. Labeling information

Compassionate Use
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3/20/2018 23
 Clinical Advisory
Committee Regulatory
Trials Review Team
Continued
APPROVAL
Reviews,
PROCESS comments, and
(Ex. FDA)
discussions
Submit to
Regulatory Agencies
Drug Co./Regulatory
liaison activities
New Drug
Application
(NDA)
APPROVAL

Worldwide Marketing Authorization (WMA) in other countries

3/20/2018 24
 Drug Discovery—Convergence of Disciplines
Synthetic
Combinatorial Patent Law
Chemistry
Chemistry
Modelling
Novel
Intellectual Property
Molecule Physiology
Information Design Structural Biochemistry
Technology
Activity
Physiology
Safety Pharmaco- Physiology
Metabolism
dynamics Pharmacology
Safety
Assessment Immunology
In Vivo activity Pharmacokinetic
Properties DMPK

Pharmacology Behavior
Pathology Enzymology
Physiology Physical Physiology
Chemistry
3/20/2018 25
 The
drug
develop
ment
process
from
discove
ry
throug
h
preclini
cal and
clinical ,
FDA
review
of the
new
drug
investig
ation
and
post
marketi
ng
surveill
ance

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