The Practice of Medicinal Chemistry

Camille Georges Wermuth, David Aldous, Pierre Raboisson, Didier Rognan

• Publisher: Academic Press
• Year: 2015
• eBook ISBN: 9780124172135
• Edition: 4
• Topic: Physical Sciences
• Subtopic: Pharmacology

The Practice of Medicinal Chemistry, Fourth Edition provides a practical and comprehensive overview of the daily issues facing pharmaceutical researchers and chemists. In addition to its thorough treatment of basic medicinal chemistry principles, this updated edition has been revised to provide new and expanded coverage of the latest technologies and approaches in drug discovery.With topics like high content screening, scoring, docking, binding free energy calculations, polypharmacology, QSAR, chemical collections and databases, and much more, this book is the go-to reference for all academic and pharmaceutical researchers who need a complete understanding of medicinal chemistry and its application to drug discovery and development.- Includes updated and expanded material on systems biology, chemogenomics, computer-aided drug design, and other important recent advances in the field- Incorporates extensive color figures, case studies, and practical examples to help users gain a further understanding of key concepts- Provides high-quality content in a comprehensive manner, including contributions from international chapter authors to illustrate the global nature of medicinal chemistry and drug development research- An image bank is available for instructors at www.textbooks.elsevier.com

Section II

Lead Compound Discovery Strategies

Outline

Chapter 4 Strategies in the Search for New Lead Compounds or Original Working Hypotheses

Chapter 5 Natural Products as Pharmaceuticals and Sources for Lead Structures*

Chapter 6 In Silico Screening: Hit Finding from Database Mining

Chapter 7 Fragment-Based Drug Discovery

Chapter 8 Molecular Variations Based on Isosteric Replacements

Chapter 9 Ring Transformations

Chapter 10 Macrocycles: Under-Explored and Poorly Exploited Drug Class Despite the Proven Therapeutic Potential

Chapter 4

Strategies in the Search for New Lead Compounds or Original Working Hypotheses

Camille G. Wermuth¹, Bruno Villoutreix², Serge Grisoni³, Anne Olivier⁴ and Jean-Philippe Rocher⁵, ¹Founder of Prestwick Chemical, Strasbourg, France, ²Université Paris Diderot Sorbonne Paris Cité, Inserm, Paris, France, ³Pierre Fabre Research Institute, Toulouse, Cédex, France, ⁴Sanofi-Aventis Recherche et Développement, Chilly-Mazarin, France, ⁵Pierre Fabre Research Institute, Castres, France

This chapter is presenting the various strategies used to find pertinent compounds as starting points for optimization up to a drug. The discovery strategies from the historical ones to the most modern approaches are reviewed. They consist into mainly five approaches: the improvement of already existing drugs, the systematic screening, the exploitation of observed biological activities, the attempts towards rational design and the target protein structure-based approaches. These strategies are not mutually exclusive and can be appropriately applied and combined.

Keywords

Lead; hits; analoging; SOSA; screening; biophysical technologies; rational design

So ist denn in der Strategie alles sehr einfach, aber darum nicht auch alles sehr leicht. (Thus in the strategy everything is very simple, but not necessarily very easy).

Carl von Clausewitz [1]

Outline

I. Introduction 73

A. Hits and Leads 74

B. The Main Hit or Lead Finding Strategies 74

II. First Strategy: Analog Design 74

A. Typical Examples 74

B. The Different Categories of Analogs 76

C. Pros and Cons of Analog Design 76

III. Second Strategy: Systematic Screening 78

A. Extensive Screening 78

B. Random Screening 79

C. High-Throughput Screening 80

D. Screening of Synthesis Intermediates 82

E. New Leads from Old Drugs: The SOSA Approach 82

IV. Third Strategy: Exploitation of Biological Information 84

A. Exploitation of Observations Made in Humans 85

B. Exploitation of Observations Made in Animals 88

C. Exploitation of Observations Made in the Plant Kingdom and in Microbiology 89

V. Fourth Strategy: Planned Research and Rational Approaches 90

A. L-DOPA and Parkinsonism 90

B. Inhibitors of the ACE 90

C. Discovery of the H₂-Receptor Antagonists 92

VI. Fifth Strategy: Applying Biophysical Technologies and Computational Methods 93

A. Biophysical Technologies 93

B. Computational Methods 94

VII. Conclusion 96

References 96

I Introduction

This chapter deals with the various strategies leading to active compounds and active compounds collections. The introduction of modern biology methods and technologies has driven the discovery process to a target-based approach. However, the discovery strategies leading to new drugs may also still address systems-based approaches such as the phenotypic screening methods [2]. The primary objective is to identify original and attractive starting points for therapeutic discovery programs. Such programs typically begin with the search for “hits.”

A Hits and Leads

A hit is an active substance having a preferential activity for the target and which satisfies all of the following criteria [3]: (1) reproducible activity in a relevant bioassay, (2) confirmed structure and high purity, (3) specificity for the target under study, (4) confirmed potential for novelty, and (5) a chemically tractable structure, that is, molecules presenting a certain affinity for a target.

Identifying hits for a new target usually involves screening of a wide range of structurally diverse small molecules in an in vitro bioassay. Alternatively, small molecules can be screened for their potential to modulate a biological process thought to be critical in disease or in which the target is thought to play a major role. Miniaturization and robotics means that the number of compounds that can be screened has greatly increased, and several thousand compounds can be screened in one day.

Once a hit is discovered, its activity must be confirmed and validated. Typical hit validation criteria are as follows: (1) the hit must be active in vitro and be amenable to in vivo activity in target or disease models; (2) the hit should not display human ether-a-go-go-related (hERG) toxicity; (3) the analogs of the hit must display clear structure–activity relationships (SAR); (4) basic physicochemical and ADME properties of the hit series must be evaluated in order to identify potential unwanted properties in the series and to assess structure–properties relationships (SPR); (5) the hit should not contain chemically reactive functions; and (6) the hit must provide patent opportunities. Only then does it becomes a lead substance, commonly named “lead.”

If a lead molecule emerges from these additional studies on SAR, absorption, distribution, metabolism, excretion (ADME), and toxicity, it acquires the “clinical drug candidate” status. After a short toxicological study, it fulfills the criteria required for administration to humans for initial clinical studies.

B The Main Hit or Lead Finding Strategies

A retrospective analysis of the ways leading to discovery of new drugs suggests that five successful strategies can yield new hits and/or lead compounds [4,5]. The first strategy is based on the modification and improvement of already existing active molecules. The second one consists of the systematic screening of sets of arbitrarily chosen compounds on selected biological assays. The third approach resides in the retroactive exploitation of various pieces of biological information that sometimes result from new discoveries made in biology and medicine, and sometimes are just the fruits of more or less fortuitous observations. The fourth route to new active compounds is a rational design based on the knowledge of the molecular cause of the pathological dysfunction. The fifth strategy is based on the structural knowledge of the target combined with computational methods or biophysical technologies of ligand–protein interaction.

II First Strategy: Analog Design

The most popular strategy in drug design is the synthesis of analogs of existing active molecule...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Foreword
• Preface to the Fourth Edition
• Preface to the Third Edition
• Preface to the Second Edition
• Preface to the First Edition
• Section I: General Aspects of Medicinal Chemistry
• Section II: Lead Compound Discovery Strategies
• Section III: Primary Exploration of Structure-Activity Relationships
• Section IV: Substituents and Functions
• Section V: Spatial Organization, Receptor Mapping and Molecular Modeling
• Section VI: Chemical Modifications Influencing the Pharmacokinetic Properties
• Section VII: Pharmaceutical and Chemical Means to Solubility and Formulation Problems
• Index