The Drug Discovery

Process
Target selection & Discovery Development
validation

Target Drug Candidate

Studies of -receptor; -ion channel; -transporter; safety testing
-enzyme; - signalling molecule
Disease Mechanisms

Lead Search
-Develop assays (use of automation) Human Studies
-Chemical diversity Phases I,II, III
Molecular Studies -Highly iterative process

Animal Studies
- relevant species
Drug Approval
- transgenic KO/KI mice Lead optimization and Registration
-selectivity
- conditional KOs
-efficacy in animal models
- agonists/antagonists
-tolerability: AEs mechanism-
- antibodies based or structure-based?
- antisense -pharmacokinetics
- RNAi -highly iterative process
 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.
 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!!!
Development
Pre-Clinical
Process R&D
Pharmacology Chem Eng. R&D
Safety Assessment Manufacturing
Toxicology
Drug Metabolism
(ADME)

Pharmaceutical R&D
Formulation Bio Process R&D

Clinical Investigator
& patient
Regulatory Affairs
Clinical Pharmacology Project Planning & Management
Clinical Research Marketing

Statistics & Epidemiology

Data Coordination
Research Information Systems
Information Services
Clinical
 Phase I Product Profile Marketing SOI
Investigational
20 - 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 Several hundred health-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
 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

 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
 Drug Discovery and development

A. Discovery of active drugs/ingredients

• Many modern drugs have been developed by imitating the naturally
occurring chemicals present in plants/animals.
• Based on the natural molecule, further research was carried out for
the synthesis of improved molecules with greater selectivity,
potency, altered duration of action, etc.
• The following are the salient features of drug discovery and
development:
1. Isolation:
• By examining the natural sources, active ingredients can be isolated, structure
identified and the pharmacological effect is determined.
Example:
 Garlic was found to be effective to low blood pressure. A lot of laboratory research
was conducted and finally diallyl sulfide, allicin, alliin and ajoene were isolated.
These compounds are found to prevent the aggregation of blood platelets.
 Ephedrine was discovered in 1887, but it attracted attention only after it came into
use in medicine as a sympathomimetic agent (commonly used as a stimulant,
appetite suppressant, concentration aid, decongestant, and to treat hypotension).
Initially it was obtained exclusively from the Chinese plant Ma Huang.

Ephedrine
2. Preparation of a molecule from synthetic method:
• Several compounds isolated from the natural sources are
being produced by synthetic route.
e.g. Ephedrine can be synthesized from propionic aldehyde,
bromine, and phenylmagnesium bromide.
• Camphor is obtained from Cinnamomum camphora, a large
evergreen tree found in Asia. It can also be synthesis by
using diethyl oxalate and 3,3-dimethylpentanoic acid.
3. Synthesis of a new molecule (analogues to existing
drugs)
Based on a molecule showing some pharmacological effect, a
new and potent molecule can be synthesized.
e.g. Aspirin can be synthesized from salicylic acid.
4. Modification in existing molecule for better potency,
absorption and duration of action:
• Benzyl penicillin is short acting, it has narrow range (can
only be used against some bacteria,
• it is typically given by a parenteral route of administration,
because it is unstable in the hydrochloric acid of the stomach.
• But now many semi synthetic penicillins, like Amoxycillin,
Cloxacillin, with longer duration of action and which can be
orally used have been produced.
• The latter compounds also contain the main β-lactam structure
present in Benzylpenicillin.
5. New applications for existing drugs
Occasionally unexpected additional properties may become
evident when the compounds are tested in humans
Sulfanilamide --> thiazide diuretics
Sulfanilamide --> sulfonylurea hypoglycemics
Aspirin® --> Anti-aggregatory --> Cardioprotective
6. Design of compounds for a specific biological function
(“Rational drug design”)
- Synthesis of naturally occurring compounds or structural
analogues
Examples: Levodopa, H2 receptor antagonists, omeprazole
- Cloning of genes to produce large biologically active
peptides
Examples: cytokines; antibodies
Approach for the synthesis of a medicinal compound
a) At first a suitable structure is estimated for the synthesis. Such structure is expected
to give a pharmacological action.
• Sometimes groups are changed or modified in a parent compound showing some
activity.
• Alcohols and carboxylic acid derivatives are the starting points for several
reactions.
• Benzene, toluene and phenol are important chemicals to produce simple aromatic
compounds.
• Cheap reagents such as water, hydrogen, sodium hydroxide, sulphuric acid are
important auxiliary materials in chemical industries.

b) After the synthesis or development of a probable compound or drug several types of

tests are carried out before using as drug (e.g. pharmacological, biochemical and
toxicological tests and clinical trials)

c) Extremely high cost of new drug development in general restricts it to the province
of large pharmaceutical companies. Cost of new drug development is in the $100 to
$500 million range. Cost of initial marketing is also very high. Incentives are very
high with important new drugs having greater than $1 Billion in yearly sales.
B. Preclinical study
1. Pharmacological studies
• After developing or synthesizing a possible new drug product, Pharmacological and
Therapeutic effects have to be established.
• Several in-vitro studies have to be conducted to find some biological or
pharmacological effects.
• These effects are determined on micro organisms, cells, tissues or isolated organs of
certain animals.
2. Toxicological studies
• If a compound shows some biological or pharmacological effect, then a possible
safe dose of the compound has to be estimated. This needs further tests in animals
(in vivo).
• Particularly the tests are related to look into the toxic dose first.
• The animal tests for toxicity are conducted prior to human clinical investigations.
• Animal test results often represent the only means by which toxicity in humans can
be effectively predicted.
• After getting an idea of toxic dose then the drug is further studied in animals in a
dose lower than the toxic dose.
• This helps to find out a possible safe dose in animals.
3. Determination of a safe dose and effect of a compound:
• According to Paracelsus the right dose differentiates a poison from a
remedy: even too much water and oxygen become poison.
• Thus to make effective drug in different dose levels are studied to
determine the threshold (latency period, No-observed adverse effect
level i.e. NOAEL) as well as dose-response relationship.
• The delay between the beginning of exposure and the appearance of
disease caused by that exposure is called the latency period.
• Usually, a minimum of three dose levels are used. In the first step
the dose response curve is determined for the acute toxicity.
• This helps to find the toxic dose.
4. Formulation of a drug into a dosage form
• Before the new drug is subjected to the further clinical evaluation,
analytical and formulation studies are conducted.
• The formulation aims to produce a stable and highly acceptable
product that delivers the current amount of drug in a reproducible
and effective manner.
• Sometimes a new drug must be modified chemically via
esterification to a prodrug in order to provide a form that is
pharmaceutically acceptable and effective.
• Stability tests are also started to estimate the conditions in which the
product will be stable.
Clinical Trial:
• If a compound has desirable activity in an experimental testing
system and appears to be safe upon toxicological examination (by
showing considerable threshold dose, latency period and NOAEL),
it becomes candidate for clinical trial.
• Two additional tasks must be accomplished, before a clinical trial
can be accomplished before a clinical trial can be undertaken.
i. the drug candidate must be in a suitable, stable dosage form, and it
must be available for absorption and transport to the site of action.
ii. file an application to the government authorities.
Phases of Clinical Trial
Phase 0

• Also called Human Micro-dosing studies.

• Gathers preliminary data Pharmacodynamics and Pharmacokinetics.
• Gives no data on safety or efficacy.
• Small number of subjects (10-15).
 Phase I
• First stage of testing in human subjects (20-100).
• Designed to assess the safety, tolerability, PK and PD of drug.
• Dose ranging – Dose escalation.
Phase 1 trials are done to find out :
Safe dosage range
Side effects
How the body copes with the drug
Patients are recruited very slowly
• This phase includes trials designed to access the
saftey
tolerability
pharmacokinetics
pharmacodynamics of drug
 Phase II
• Therapeutic Exploratory Trial. (20-300 Subjects).
• Efficacy in patients (primary objective)
• Safety issues (secondary objective)
• Optimum dose finding
• Phase II
• Phase IIA: Designed to assess dosing requirements
• Phases IIB: Designed to study efficacy
 Phase III
• Therapeutic confirmatory trials. (300-3000 subjects).
• To establish efficacy of the drug against existing therapy
in larger number of patients, method of usage etc.,.
• Subtypes
• Phase IIIA: to get sufficient and significant data.
• Phase IIIB: allows patients to continue the treatment,
Label expansion, additional safety data.
Phase IV
• Post Marketing Studies (PMS).
• Involves safety surveillance.
• Determine behavior of drug in real life situations.
• Evaluate action of drug in a situation of missed dosage or over dosage.
• Phase IV
• Phase IV trial is also known as Postmarketing surveillance Trial. Phase IV
trials involve the safety surveillance (pharmacovigilance) and ongoing
technical support of a drug after it receives permission to be sold. Phase IV
studies may be required by regulatory authorities or may be undertaken by
the sponsoring company for competitive (finding a new market for the drug)
or other reasons (for example, the drug may not have been tested for
interactions with other drugs, or on certain population groups such as
pregnant women, who are unlikely to subject themselves to trials). The
safety surveillance is designed to detect any rare or long-term adverse
effects over a much larger patient population and longer time period than
was possible during the Phase I-III clinical trials. Harmful effects discovered
by Phase IV trials may result in a drug being no longer sold, or restricted to
certain uses