1. The Drug Discovery Process
Target selection &
validation
Discovery
Development
Target
-receptor; -ion channel; -transporter; -enzyme; - signalling molecule
Studies of Disease Mechanisms
Drug Candidate
safety testing
Human Studies
Phases I,II, III
Lead Search
-Develop assays (use of automation)
-Chemical diversity
-Highly iterative process
The Drug Discovery Process
Molecular Studies
Drug Approval
and Registration
Lead optimization
-selectivity
-efficacy in animal models
-tolerability: AEs mechanism-
based or structure-based? -pharmacokinetics
-highly iterative process
Animal Studies
- relevant species
- transgenic KO/KI mice
- conditional KOs
- agonists/antagonists
- antibodies
- antisense
- RNAi

2. 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.
Here is what we are trying to achieve (refer to slide).
Note that you can comment on:
We conduct basic animal health research in RY, but our animal health care products are marketed by Merial, a joint venture between Merck and Rhone- Poulenc (note that RP is now known as Aventis (RP merged with Hoechst).
Outcomes research is when we attempt to prove that our compounds not only cause important chemical effects in the body (such as reduced blood pressure or reduced cholesterol), but that these effects lead to reduced morbidity and mortality over time. The Zocor 4S study is an example.
The research budget for MRL is $2.4 billion this year.

3. 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”)
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!!!
Here is what we are trying to achieve (refer to slide).
Note that you can comment on:
We conduct basic animal health research in RY, but our animal health care products are marketed by Merial, a joint venture between Merck and Rhone- Poulenc (note that RP is now known as Aventis (RP merged with Hoechst).
Outcomes research is when we attempt to prove that our compounds not only cause important chemical effects in the body (such as reduced blood pressure or reduced cholesterol), but that these effects lead to reduced morbidity and mortality over time. The Zocor 4S study is an example.
The research budget for MRL is $2.4 billion this year.

4. Development Pre-Clinical Clinical Process R&D Chem Eng. R&D
Manufacturing
Bio Process R&D
Safety Assessment
Toxicology
Drug Metabolism
(ADME)
Pharmacology
Pharmaceutical R&D
Formulation
Regulatory Affairs
Project Planning & Management
Marketing
Clinical Investigator
& patient
Clinical Pharmacology
Clinical Research
Statistics & Epidemiology
Data Coordination
Research Information Systems
Information Services

5. IND Clinical Trials Phase I Phase II Phase III Investigational
healthy volunteers take drug for about one month
Remote data entry
Product Profile Marketing SOI
Information Learned
1. Absorption and metabolism
2. Effects on organs and tissue
3. Side effects as dosage is increased
Investigational
New Drug
application
IND
Clinical Trials
Phase II
Several hundred health-impaired patients
Treatment Group
Control Group
Information Learned
1. Effectiveness in treating disease
2. Short-term side effects in health -impaired patients
3. Dose range
Phase III
Hundreds or thousands of health-impaired patients
Information Learned
1. Benefit/risk relationship of drug
2. Less common and longer term side effects
3. Labeling information
Compassionate Use

6. Worldwide Marketing Authorization (WMA) in other countries
Advisory
Committee
Clinical Trials Continued
Regulatory
Review Team
APPROVAL
PROCESS
(Ex. FDA)
Reviews,
comments, and
discussions
Submit to
Regulatory Agencies
New Drug
Application
(NDA)
APPROVAL
Drug Co./Regulatory
liaison activities
Worldwide Marketing Authorization (WMA) in other countries

7. Drug Discovery—Convergence of Disciplines
Combinatorial
Chemistry
Synthetic
Physical
Patent Law
Information
Technology
Modelling
Novel
Molecule
Intellectual Property
Structural
Activity
Pharmacokinetic
Properties
In Vivo activity
Safety
Design
Pharmaco-
dynamics
Physiology
Biochemistry
DMPK
Enzymology
Immunology
Pharmacology
Physiology
Physiology
Safety
Assessment
Metabolism
Pharmacology
Pathology
Behavior
Physiology
Physiology