The Practice of Medicinal Chemistry - 4th Edition - ISBN: 9780124172050, 9780124172135

The Practice of Medicinal Chemistry

4th Edition

Editors: Camille Wermuth David Aldous Pierre Raboisson Didier Rognan
Hardcover ISBN: 9780124172050
eBook ISBN: 9780124172135
Imprint: Academic Press
Published Date: 17th July 2015
Page Count: 902
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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.

Key Features

  • 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


Professors of medicinal chemistry, medicinal chemistry students and pharmaceutical researchers engaged in drug discovery

Table of Contents

  • 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
    • Chapter 1. Medicinal Chemistry: Definitions and Objectives, Drug Activity Phases, Drug Classification Systems
      • I Definitions and Objectives
      • II Drug Activity Phases
      • III Drug Classification Systems
      • References
    • Chapter 2. Evaluation of the Biological Activity of Compounds: Techniques and Mechanism of Action Studies
      • I Introduction
      • II Drug Discovery Approaches and Screening Cascades
      • III In Vitro Assays
      • IV Ex Vivo Assays
      • V In Vivo Assays
      • Acknowledgements
      • References
    • Chapter 3. Drug Targets, Target Identification, Validation, and Screening
      • I Introduction
      • II What is a Drug Target?
      • III The Purpose of Target Identification
      • IV Target Options and Treatment Options
      • V Target Deconvolution and Target Discovery
      • VI Methods for Target Identification and Validation
      • VII Target Validation
      • VIII Conclusion
      • References
  • Section II: Lead Compound Discovery Strategies
    • Chapter 4. Strategies in the Search for New Lead Compounds or Original Working Hypotheses
      • I Introduction
      • II First Strategy: Analog Design
      • III Second Strategy: Systematic Screening
      • IV Third Strategy: Exploitation of Biological Information
      • V Fourth Strategy: Planned Research and Rational Approaches
      • VI Fifth Strategy: Applying Biophysical Technologies and Computational Methods
      • VII Conclusion
      • References
    • Chapter 5. Natural Products as Pharmaceuticals and Sources for Lead Structures
      • I Introduction
      • II The Importance of Natural Products in Drug Discovery and Development
      • III The Design of an Effective Natural-Products-Based Approach to Drug Discovery
      • IV Examples of Natural Products or Analogues as Drugs
      • V Future Directions in Natural Products as Drugs and Drug Design Templates
      • VI Summary
      • References
    • Chapter 6. In Silico Screening: Hit Finding from Database Mining
      • I Introduction
      • II In Silico Screening
      • III De Novo Design
      • IV Conclusions and Future Directions
      • Glossary
      • References
    • Chapter 7. Fragment-Based Drug Discovery
      • I Ligand–Protein Interactions: First Principles
      • II What is Fragment-Based Drug Discovery?
      • III Creation and Analysis of FBDD Libraries
      • IV Fragment Screening Methods
      • V Other Biochemical and Biophysical Methods
      • VI Fragment Merging/Linking/Growing
      • VII Fragment Hit Follow-Up, and Pitfalls to Avoid
      • VIII Zelboraf®, First Approved Drug from FBDD
      • IX Limitations of FBDD
      • X Trends for the Future
      • References
    • Chapter 8. Molecular Variations Based on Isosteric Replacements
      • I Introduction
      • II History: Development of the Isosterism Concept
      • III Currently Encountered Isosteric and Bioisosteric Modifications
      • IV Scaffold Hopping
      • V Analysis of the Modifications Resulting from Isosterism
      • VI Minor Metalloids-Toxic Isosteres
      • References
    • Chapter 9. Ring Transformations
      • I Introduction
      • II Analogical Approaches
      • III Disjunctive Approaches
      • IV Conjunctive Approaches
      • V Conclusion
      • References
    • Chapter 10. Macrocycles: Under-Explored and Poorly Exploited Drug Class Despite the Proven Therapeutic Potential
      • I Nature as a Source of Macrocycles
      • II Identification of Macrocyclic Drugs Using Either Phenotypic Screen or Target-Based Approach
      • III Macrocycles: The Drugs in the Middle Space
      • IV Effect of the Macrocyclization on Drug-Like Properties
      • V Interaction of Macrocycles with their Targets
      • VI Synthesis of Macrocycles & Library Enrichment
      • VII Conclusion
      • References
  • Section III: Primary Exploration of Structure-Activity Relationships
    • Chapter 11. Conformational Restriction and Steric Hindrance in Medicinal Chemistry
      • I Introduction
      • II Case Studies
      • III Summary and Outlook
      • References
    • Chapter 12. Application Strategies for the Primary Structure–Activity Relationship Exploration
      • I Introduction
      • II Preliminary Considerations
      • III Hit Optimization Strategies
      • IV Application Rules
      • References
    • Chapter 13. Substituent Groups
      • I Introduction
      • II Methyl Groups
      • III Effects of Unsaturated Groups
      • IV Effects of Halogenation
      • V Effects of Hydroxylation
      • VI Effects of Thiols and Other Sulfur-Containing Groups
      • VII Acidic Functions
      • VIII Basic Groups
      • IX Attachment of Additional Binding Sites
      • References
    • Chapter 14. The Role of Functional Groups in Drug–Receptor Interactions
      • I Introduction
      • II General Principles
      • III The Importance of the Electrostatic and Steric Match Between Drug and Receptor
      • IV The Strengths of Functional Group Contributions to Drug–Receptor Interactions
      • V Cooperative Binding
      • References
    • Chapter 15. Compound Properties and their Influence on Drug Quality
      • I Introduction
      • II Compound Drug-Likeness Analysis
      • III Compound Promiscuity
      • IV Compound ADMET Properties
      • V Ligand Binding Efficiency Metrics
      • VI Conclusions and Future Outlook
      • References
    • Chapter 16. Pharmacological Space
      • I What is Pharmacological Space?
      • II Chemical Space
      • III Target Space
      • IV Conclusions
      • Acknowledgments
      • References
    • Chapter 17. Systems Biology: A New Paradigm for Drug Discovery
      • I Introduction
      • II Drug-Target Space (off-target)
      • III Systems Biology Space
      • IV Phenotype Space
      • V Examples
      • VI Conclusion
      • References
  • Section IV: Substituents and Functions
    • Chapter 18. Optical Isomerism in Drugs
      • I Introduction
      • II Experimental Facts and their Interpretation
      • III Optical Isomerism and Pharmacodynamic Aspects
      • IV Optical Isomerism and Pharmacokinetic Aspects
      • V Practical Considerations
      • References
    • Chapter 19. Multitarget Drugs: Strategies and Challenges for Medicinal Chemists
      • I Introduction
      • II Strategies for Lead Generation
      • III Main Areas of Focus in Discovery
      • IV Optimization of the Activity Profile and Wider Selectivity
      • V The Physicochemical Challenge
      • VI Summary
      • References
    • Chapter 20. Selective Optimization of Side Activities (SOSA) in Drug Discovery
      • I Introduction
      • II Ritonavir: Rejuvenating a Suboptimal Drug
      • III Sildenafil, Side Effects are Not Always Bad
      • IV Nucleotide Prodrugs: Chemical Trojan Horses
      • V Miltefosine
      • VI Aztreonam
      • VII Conclusions
      • References
  • Section V: Spatial Organization, Receptor Mapping and Molecular Modeling
    • Chapter 21. Pharmacophore Identification and Pseudo-Receptor Modeling
      • I Introduction
      • II Methodology
      • III Advanced Approaches
      • IV Application Study: Novel Histamine H3-Receptor Antagonists
      • V Recent Developments and Outlook
      • VI Conclusions
      • References
    • Chapter 22. Protein Crystallography and Drug Discovery
      • I Introduction
      • II Historical Background
      • III Basic Principles and Methods of Protein Crystallography
      • IV Applications
      • V Two Selected Examples
      • VI Outlook
      • References
    • Chapter 23. Physiological Aspects Determining the Pharmacokinetic Properties of Drugs
      • I Introduction
      • II Passage of Drugs Through Biological Barriers
      • III Drug Absorption
      • IV Drug Distribution
      • V Drug Elimination
      • VI Some Pharmacokinetic Parameters and Terminology
      • VII Variability in Pharmacokinetics
      • Further Reading
    • Chapter 24. Biotransformation Reactions and their Enzymes
      • I Introduction
      • II Functionalization Reactions
      • III Conjugation Reactions
      • IV Biological Factors Influencing Drug Metabolism
      • V What is the Relative Significance of These Many Types of Metabolic Reactions?
      • VI Concluding Remarks
      • References
    • Chapter 25. Biotransformations Leading to Toxic Metabolites: Chemical Aspects
      • I Historical Background
      • II Introduction
      • III Reactions Involved in Bioactivation Processes
      • IV Examples of Metabolic Conversions Leading to Toxic Metabolites
      • V Conclusion
      • Acknowledgments
      • References
    • Chapter 26. Drug Transport Mechanisms and their Impact on the Disposition and Effects of Drugs
      • I Introduction
      • II Biology and Function of Transporters
      • III Transporters in Drug Disposition
      • IV Roles of Transporters in Drug Pharmacokinetics, Pharmacodynamics and Toxicology
      • V Conclusion
      • Acknowledgments
      • References
    • Chapter 27. Strategies for Enhancing Oral Bioavailability and Brain Penetration
      • I Introduction
      • II Enhancing Oral Bioavailability
      • III Enhancing Brain Penetration
      • References
    • Chapter 28. Designing Prodrugs and Bioprecursors
      • I Introduction
      • II The Different Kinds of Prodrugs
      • III Practical Applications of Carrier Prodrugs
      • IV Unique Approaches to Carrier Prodrug Design
      • V Bioprecursor Prodrug Examples
      • VI Discussion
      • VII Difficulties and Limitations
      • VIII Conclusion
      • References
  • Section VI: Chemical Modifications Influencing the Pharmacokinetic Properties
    • Chapter 29. Drug Delivery with Organic Solvents or Colloidal Dispersed Systems
      • I Introduction
      • II Physicochemical Drug Properties
      • III Oral Drug Delivery
      • IV Parenteral Drug Delivery
      • References
    • Chapter 30. Preparation of Water-Soluble Compounds by Covalent Attachment of Solubilizing Moieties
      • I Introduction
      • II Solubilization Strategies
      • III Acidic Solubilizing Chains
      • IV Basic Solubilizing Chains
      • V Nonionizable Side Chains
      • VI Concluding Remarks
      • References
    • Chapter 31. Improving the Water-Solubility of Compounds by Molecular Modification to Disrupt Crystal Packing
      • I Introduction
      • II Rationale for Disruption of Crystal Packing as an Alternative Method to Improve Solubility
      • III Improvement of Solubility by Disrupting Intermolecular Hydrogen Bonds
      • IV Improvement of Solubility by Disrupting Molecular Planarity
      • V Improvement of Solubility by Bending the Molecular Structure
      • VI Advantages of Improving Solubility by Molecular Modification to Weaken Intermolecular Interaction
      • VII Conclusion
      • References
    • Chapter 32. Chemical and Physicochemical Approaches to Solve Formulation Problems
      • I Introduction
      • II Stability
      • III Bioavailability
      • IV Modifying the Duration of Action
      • V Manufacturing Issues
      • VI Adapting to Patient’s Needs
      • References
    • Chapter 33. Discover a Drug Substance, Formulate, and Develop It to a Product
      • I Introduction
      • II The Discovery Phase
      • III Defining Experimental Formulations, the Creative Phase
      • IV Preparation for a New Drug-Product Launch
      • V Conclusion: Drug Discovery and Development in Industry
      • Reference
  • Section VII: Pharmaceutical and Chemical Means to Solubility and Formulation Problems
    • Chapter 34. Drug Nomenclature
      • I Introduction
      • II Trade Names and Nonproprietary Names
      • III Drug Nomenclature
      • IV Use and Protection of Nonproprietary Names
      • V Summary
      • References
      • Annex
    • Chapter 35. Web Alert: Using the Internet for Medicinal Chemistry
      • I Introduction
      • II Blogs
      • III Wikis
      • IV Compound Information
      • V Biological Properties of Compounds
      • VI Drug Information
      • VII Physical Chemical Information
      • VIII Prediction and Calculation of Molecular Properties
      • IX Chemical Suppliers
      • X Chemical Synthesis
      • XI Chemoinformatics Software Programs
      • XII Chemical Analysis
      • XIII Chemical Publications
      • XIV Patent Information
      • XV Toxicology
      • XVI Meta-Sites and Technology Service Provider Databases
      • XVII Conclusion
    • Chapter 36. Protection of Inventions in Medicinal Chemistry
      • I Patents and the Medicinal Chemist
      • II What Kinds of Medical Inventions can be Patented?
      • III The Basics of Patent Law
      • IV The Role of the Medicinal Chemist in the Patent Arena
      • V Patents as a Source of Scientific Information
      • VI Other Forms of Protection
      • VII Conclusion
  • Index


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© Academic Press 2015
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About the Editor

Camille Wermuth

Camille-Georges Wermuth PhD, Prof. and Founder of Prestwick Chemical, was Professor of Organic Chemistry and Medicinal Chemistry at the Faculty of Pharmacy, Louis Pasteur University, Strasbourg, France from 1969 to 2002. He became interested in Medicinal Chemistry during his two years of military service in the French Navy at the "Centre d’Etudes Physio-biologiques Appliquées à la Marine" in Toulon. During this time he worked under the supervision of Dr Henri Laborit, the scientist who invented artificial hibernation and discovered chlorpromazine.

Professor Wermuths’ main research themes focus on the chemistry and the pharmacology of pyridazine derivatives. The 3-aminopyridazine pharmacophore, in particular, allowed him to accede to an impressive variety of biological activities, including antidepressant and anticonvulsant molecules; inhibitors of enzymes such as mono-amine-oxidases, phosphodiesterases and acetylcholinesterase; ligands for neuro-receptors: GABA-A receptor antagonists, serotonine 5-HT3 receptor antagonists, dopaminergic and muscarinic agonists. More recently, in collaboration with the scientists of the Sanofi Company, he developed potent antagonists of the 41 amino-acid neuropeptide CRF (corticotrophin-releasing factor) which regulates the release of ACTH and thus the synthesis of corticoids in the adrenal glands. Professor Wermuth has also, in collaboration with Professor Jean-Charles Schwartz and Doctor Pierre Sokoloff (INSERM, Paris), developed selective ligands of the newly discovered dopamine D3 receptor. After a three-year exploratory phase, this research has led to nanomolar partial agonists which may prove useful in the treatment of the cocaine-withdrawal syndrome.

Dr. Wermuth is co-author or editor of several books, the author of over 250 scientific papers and holds nearly 60 patents. Professor Wermuth is also the recipient of the Charles Mentzer Prize of the Société Française de Chimie Thérapeutique, the Léon Velluz Prize of the French Academy of Science, the Prix de l'Ordre des Pharmaciens by the French Academy of Pharmacy and the Nauta Award of the European Federation for Medicinal Chemistry for Pharmacochemistry in 2010.

Affiliations and Expertise

Prestwick Chemical, Illkirch, France

David Aldous

Affiliations and Expertise

Head, LGCR Boston, Sanofi, Boston, MA

Pierre Raboisson

Affiliations and Expertise

Senior Director, Fellow and Head of Infectious Diseases and Vaccines Medicinal Chemistry, Janssen, Pharmaceutical Companies of Johnson & Johnson, Beerse, Belgium

Didier Rognan

Affiliations and Expertise

Research Director, Laboratoire d'Innovation Thérapeutique, Université de Strasbourg, France


"...So that you are a young student of a faculty in the field of pharmacology looking for a formative text, a young researcher at the beginning of his or her experiential work or an expert in the "drug discovery" industry that only wants to deepen theme specifications, most likely in this book you will find what you need." (Google translation) --La Chimica e l’Industria

"...provides a diverse, multi-authored yet comprehensive update on the current state of the art in the science of medicinal chemistry…highly recommended for graduate students in the medicinal chemistry and drug discovery sciences." --Drug Development Research

Praise for the Third Edition:
"The third edition of this book, useful to seasoned medicinal chemists as well as to chemists entering the academic or industrial laboratories, provides a hands-on overview of the drug discovery process. This edition differs from the previous two editions by having been updated to reflect developments in the past 5 years, and it includes 11 new chapters. I found this book to be unique, well organized, and overall a useful addition to the medicinal chemistry literature. Having favorably reviewed the first edition, I still highly recommend this third edition to all chemists who are involved in the drug discovery process." --John L. Neumeyer, Harvard Medical School, Journal of Medicinal Chemistry

"...a diverse, multi-authored yet comprehensive update on the current state of the art in the science of medicinal chemistry...highly recommended for graduate students in the medicinal chemistry and drug discovery sciences."--Drug Development Research,The Practice of Medicinal Chemistry, Fourth Edition

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