Drug design and development

1
Drug design and development
Stages
1) Identify target disease 2) Identify drug
target 3) Establish testing procedures 4) Find
a lead compound 5) Structure Activity
Relationships (SAR) 6) Identify a pharmacophore
7) Drug design- optimizing target interactions
8) Drug design - optimizing pharmacokinetic
properties 9) Preclinical trials 10) Chemical
development and process development 11) Patenting
and regulatory affairs 12) Clinical trials
Note Stages 9-11 are usually carried out in
parallel
2
9. Preclinical trials

Drug Metabolism Identification of drug
metabolites in test animals Properties of drug
metabolites Toxicology In vivo and in vitro
tests for acute and chronic toxicity
Pharmacology Selectivity of action at drug
target Formulation Stability tests Methods
of delivery
3
10. Chemical Development
Phases

• Synthesis of 1 kg for initial preclinical testing
  (often a scale up of the original synthesis)
  
• Synthesis of 10 kg for toxicological studies,
  formulation and initial clinical trials
• Synthesis of 100 kg for clinical trials
• Notes
• Chemical development is more than just scaling up
  the original synthesis
• Different reaction conditions or synthetic routes
  often required
• Time period can be up to 5 years
• Need to balance long term aims of developing a
  large scale synthesis versus short term need for
  batches for preclinical trials
• The product produced by the fully developed route
  must meet the same specifications as defined at
  phase 1

4
10. PROCESS DEVELOPMENT

• DEFINITION
• Development of the overall synthetic route to
  make it suitable for
• the production site and can produce batches of
  product in ton
• quantities with consistent yield and purity
• PRIORITIES
• Minimizing the number of reaction steps
• The use of convergent syntheses
• Minimizing the number of operations
• Integration of the overall reaction scheme
• Safety - chemical hazards
• Safety - reaction hazards
• Minimising the number of purification steps
• Environmental issues
• Cost

5
11. PATENTING AND REGULATORY AFFAIRS

• PATENTING
• Carried out as soon as a potentially useful drug
  is identified
• Carried out before preclinical and clinical
  trials
• Cannot specify the exact structure that is likely
  to reach market
• Patent a group of compounds vs. an individual
  structure
• Can cover specific product, medical uses of
  product, and/or
• synthesis of product

6
11. PATENTING AND REGULATORY AFFAIRS

• REGULATORY AFFAIRS
• Drug must be approved by regulatory bodies
• Food and Drugs Administration (FDA)
• European Agency for the Evaluation of Medicinal
  Products (EMEA)
• Proper record keeping is essential
• GLP - Good Laboratory Practice
• GMP - Good Manufacturing Practice
• GCP - Good Clinical Practice

7
12.Clinical Trials
Phase I (3-18 months) - evaluates safety,
tolerability, pharmokinetics, and pharmacological
effects in 20-200 healthy volunteers Phase II
(1-3 years) - assesses effectiveness, determines
side effects and other safety aspects, clarifies
dosing in a few hundred patients Phase III (2-6
years) - establishes efficacy and adverse effects
from long-term use with thousands of patients New
Drug Application (NDA) submitted to FDA (4-36
months) Phase IV - results after drug is on
market- established long term effects and unusual
side effects