DRUG DISCOVERY,

DESIGN AND
DEVELOPMENT

Louis Daniele L. Bernardo, RPh, RChT

Pharmaceutical and Medicinal Organic Chemistry
Brief History
• Ancient people used natural products as
drugs – however, many of the products were
very toxic
• Tartar emetic: banned in Paris on 1566
• 19th Century: Extraction of pure substances
from natural products
• Few of the compounds isolated proved to be
satisfactory as therapeutic agents
• Majority discovered were too toxic
Brief History
• The search to find less toxic substances
than those based on natural sources
resulted in the introduction of synthetic
substances as drugs → LEADS
Drug Discovery, design and
Development: The Present
1. Finding the lead
2. Drug Design
3. Drug Development
FINDING THE LEAD
 Finding the Lead
1. Choose the disease
2. Choose a drug target
3. Identify a bioassay
4. Find a “lead compound”
5. Isolate and purify the lead compound if necessary
6. Determine the structure of the lead compound if
necessary
 1. Choose a Disease
• Market first, science follows
• A huge investment has to be made in the
research and development of a new drug.
• Considerations:
• Economic
• Medical
 2. Drug Target
• An understanding of which
biomacromolecules are involved in a
particular disease state is clearly important.
 3. Identify a Bioassay
• The test should be simple, quick, and
relevant, as there are usually a large number
of compounds to be analyzed.
• Human testing is not possible at such an
early stage
• In vitro test first, then in vivo
 3. Identify a Bioassay
• In vitro Tests
• In vitro tests do not involve animals
• Specific tissues, cells, or enzymes are used
 3. Identify a Bioassay
• In vivo tests
• In vivo tests on animals often involve inducing a
clinical condition in the animal to produce
observable symptoms
• In vivo tests are often needed to check whether
drugs have the desired pharmacological activity
and also to monitor their pharmacokinetic
properties
 4. Finding the LEAD Compound
• Lead compound is a compound which shows
the desired pharmacological activity.
• The lead compound provides a start for the
drug design and development process.
Natural Products Screening
• Most biologically active natural products are
secondary metabolites with quite complex
structures and several chiral centers.
• The study of medicines derived from natural
sources is known as pharmacognosy.
Natural Products Screening
• Sources:
• Plants
• Microorganisms
• Marine life
• Animals
• Venoms and toxins
Medical Folklore
• Traditional/folkloric claims
Screening Synthetic Compound
Libraries
• Pharmaceutical companies often screen their
library of compounds whenever they study a
new target.
• Pharmaceutical companies often try to
diversify their range of structures by
purchasing novel compounds prepared by
research groups elsewhere.
Existing Drugs
• “Me too” and “Me better” Drugs
• Many companies use established drugs from
their competitors as lead compounds
• AIM: To modify the structure sufficiently
such that it avoids patent restrictions, retains
activity, and ideally, has improved
therapeutic properties.
• Example: Captopril
Computer-aided Design
• Molecular modelling software programs can
be used to study the binding site and to
design molecules which will fit and bind to
the site (de novo drug design)
Serendipity
• Frequently, lead compounds are found as a
result of serendipity (i.e. chance)
 4. Find a LEAD Compound
• Ways to discover a LEAD compound:
1. Natural Products Screening
2. Medical Folklore
3. Screening Synthetic Compound Libraries
4. Existing Drugs
5. Computer-aided Design
6. Serendipity
 5. Isolation and Purification
• If the lead compound (or active principle) is
present in a mixture of compounds from a
natural source or a combinatorial synthesis,
it has to be isolated and purified.
 6. Structure Elucidation
• Structure determination is a relatively
straightforward process and it is only when
the natural product is obtained in minute
quantities that a full synthesis is required to
establish its structure.
 Drug Discovery, Design, and
Development: The Present
1. Finding the Lead
2. Drug Design
3. Drug Development
DRUG DESIGN
Drug Design
1. Identify structure-activity relationships (SARs)
2. Identify the pharmacophore
3. Improve target interactions
(pharmacodynamics)
4. Improve pharmacokinetic properties
 1. SAR
• Structure Activity Relationship (SAR)
• Relationship of how structural features of the
molecule contribute to, or take away from, the
desired biologic activity
• SAR Studies are essential in drug optimization
• To find analogues with better activity and
selectivity
 2. Pharmacophore
• Summarizes the important binding groups
that are required for activity, and their
relative positions in space with respect to
each other.
Drug Optimization
• Pharmacodynamic optimization
• Pharmacokinetic optimization
DRUG DEVELOPMENT
Stages of Drug Development
Investigational New Drug
• The application submitted for obtaining permission
to start human clinical trials and to ship
experimental drug across state lines before a
marketing application for a drug has been
approved.
• Data showing reasonable results must be
submitted to begin testing the drug on humans.
New Drug Application
• The application submitted to FDA for obtaining
permission to market a new drug.
• Preclinical and clinical test data on animal and
human studies, pharmacology of the drug,
toxicology, and dosage, and contains information
about the drug’s manufacturing process.
 Abbreviated New Drug
Application
• Used to gain approval to market a generic
equivalent of a product that is already approved
and being marketed by the pioneer, or the original
sponsor, of the drug.
 Phases of Clinical Trials
• PHASE I
• Determines drug safety
• Use of healthy volunteers
• Sample size: 20-100 healthy persons
• PHASE II
• Determine drug safety and efficacy
• Hospital setting
• Sample size: 100-1000
• Phase II-a – dose response and dose ranging
• Phase II-b – dose determination studies
 Phases of Clinical Trials
• PHASE III
• Usefulness of drug determination
• Hospital setting (Tertiary hospitals)
• Sample size: 1000 to several thousand
• PHASE IV
• Post-marketing
• Clinical pharmacology/toxicity testing
• Additional indications