C.G. WERMUTH, Introductory Course in Medicinal Chemistry 15/10/01

INTRODUCTORY COURSE IN MEDICINAL CHEMISTRY

 

 

PART 1 - DEFINITIONS AND GENERAL TOPICS. DISCOVERY AND IDENTIFICATION OF NEW LEAD COMPOUNDS

 

Definitions of the terms « Drug » and « Medicinal Chemistry.

What Exactly is a Drug?

What is Medicinal Chemistry

 

The three critical steps in the development of a new drug substance.

The Pharmaceutical Phase

The Pharmacokinetic Phase

The Pharmacodynamic Phase

 

Drug Development Flow Schemes

The Traditional Flow Scheme

Present Development Strategies

 

The Origin of New Lead Substances or Working Hypotheses

First Strategy: Improvement of Already Existing Drugs

Second Strategy: Systematic screening

Third Strategy: Exploitation of New Biological or Medical Discoveries

Fourth Strategy: Planned Research and Rational Approaches

Conclusion: Sweat, Luck and Serendipity

 

PART 2 – PRACTICAL ASPECTS OF DRUG OPTIMIZATION.

 

Strategies for the Exploration of the Primary Structure-Activity Relationships

Disjunctive Approaches

Analogical Approaches

Conjunctive Approaches

 

Homologous Series in Medicinal Chemistry

Classification of Homologous Series

Shapes of the Biological Response Curves

Discussion

 

Vinylogues and benzologues

Definitions and Classification

Examples

Comments

 

Molecular variations based on isosteric replacements

 

History: The Development of the Isosterism Concept

Grimm’s Hydride Displacement Law

Erlenmeyers Expansion of the Isosterism Concept

Bioisosterism and Present Conceptions of Isosterism

 

Currently Encountered Isosteric and Bioisosteric Modifications

Replacement of Univalent Atoms and Groups

Interchange of Divalent Atoms and Groups

Interchange of Trivalent Atoms and Groups

Ring Equivalents

Isosteric Replacements of Heterocycles

 

Groups with Similar Polar Effects

            Surrogates of the Carboxylic Acid Function

            Surrogates of the Ester Function

            Amides and Peptides

            Urea and Thiourea Equivalents

 

Reversal of Functional Groups

 

Analysis of the Modifications Resulting from Isosterism

 

Anomalies in Isosterism

            Fluorine-Hydrogen Isosterism

The Friedman Paradox

 

Minor metalloids-Toxic isosteres

Carbon-Silicon Isosterism

Carbon-Boron Isosterism

 

Ring Transformations

Analogical Approaches

Disjunctive Approaches

Conjunctive Approaches

Conformational Restriction

Discussion

 

Associative Synthesis

Spacing and Connection Modes

Identical and Non-Identical Twin-Drugs

Discussion: Scope and Limitations of Associative Synthesis

 

Substituent Effects

Conformational Effects

Lipophilic Effects

Electronic effects

Substituents and QSAR: Selection of the Right Substituent

Lipinski’s “Rule of Five”

 

 

 

Exercice: The Systematic Application Stratagem in the Daily Practice

 

 

Drug Optimization: The Application Rules

 

Rule Number One: The Minor Modifications Rule

Rule Number Two: The Biological Logic’s Rule

Rule Number Three: The Structural Logic’s Rule

Rule Number Four: The Right substituent Choice

Rule Number Five: The Easy Organic Synthesis (“EOS”) Rule

Rule Number Six: Eliminate the Chiral Centers

Rule Number Seven: The Pharmacological Logic’s Rule

 

 

PART 3 – CHEMICAL ASPECTS OF DRUG FORMULATION

 

Designing Prodrugs and Bioprecursors

General aspects and definitions

1 – Carrier Prodrugs

The Carrier Prodrug Principle

An example of Carrier Prodrug Design

Practical Applications of Prodrug Design

            Improvement of the Bioavailability and the Biomembrane Passage

            Site-Specific Delivery

            Prolonged Duration of Action

Use of Cascade Prodrugs

2 – Bioprecursors

Drug Metabolism : the Basis for Bioprecursor Design

Oxidative Bioactivations

Reductive Bioactivations

Mixed Activation Mechanisms

3 – Discussion

Bioprecursors versus Carrier Prodrugs

Existence of Mixed-Type Prodrugs

Difficulties and Limitations of the Prodrug Approach

 

Chemical and Physico-Chemical Solutions to Formulation Problems

Increasing Chemical Stability

Improved Formulation of Peptides and Proteins

Dealing with Mesomorphic Crystalline Forms

Transforming Liquids into Solids

Dealing with Gastrointestinal Irritation and Painful Injections

Suppression of Undesirable Organoleptic Properties

Appendix: Selected Procedures for Preparing Hydrochlorides and Na or K Salts

 

Preparation of Water-Soluble Compounds by Covalent Attachment of Solubilizing Moieties

Possible Solubilization Strategies

Acylation of OH and NH Functions with Acidic Chains

Phosphate Esters

Sulfate Esters

Acidic and Basic Oximes

Solubilization by Means of Basic Side Chains

            Dialkylglycines and Related Aminoesters

Non-Ionizable Side Chains

Glucosides and Related Compounds

Concluding remarks