The Practice of Medicinal Chemistry The Medicinal Chemist's Bible

Now in its third edition, this classic reference is the one-stop-shop for information on the foundations of medicinal chemistry for pharmaceutical researchers who are involved in drug development & discovery but do not have a background in medicinal chemistry. Wermuth aids pharmaceutical researchers and chemists in making faster more accurate identifications of the active substances that could potentially treat the disorder they are researching. New chapters on Drug Absorption & Transport, give pharmaceutical scientists the information on how potential drugs can move through the drug discovery/ development phases more quickly. This third edition still stands as the only source for practical aspects of medicinal chemistry by focusing on the daily problems met by the medicinal chemist in drug discovery.

The Practice of Medicinal Chemistry fills a gap in the list of available medicinal chemistry literature. It is a single-volume source on the practical aspects of medicinal chemistry. Considered ""the Bible"" by medicinal chemists, the book emphasizes the methods that chemists use to conduct their research and design new drug entities. It serves as a practical handbook about the drug discovery process, from conception of the molecules to drug production. The first part of the book covers the background of the subject matter, which includes the definition and history of medicinal chemistry, the measurement of biological activities, and the main phases of drug activity. The second part of the book presents the road to discovering a new lead compound and creating a working hypothesis. The main parts of the book discuss the optimization of the lead compound in terms of potency, selectivity, and safety. The Practice of Medicinal Chemistry can be considered a ""first-read"" or ""bedside book"" for readers who are embarking on a career in medicinal chemistry.

Biography
Section Editors
Contributors
Preface to the First Edition
Preface to the Second Edition
Preface to the Third Edition

Part I General Aspects of Medicinal Chemistry
1. A History of Drug Discovery
I. Introduction
II. Two Hundred Years of Drug Discoveries
III. Considerations on Recent Trends in Drug Discovery
References

2. Medicinal Chemistry: Definitions and Objectives, Drug Activity Phases, Drug Classification Systems
I. Definitions and Objectives
II. Drug Activity Phases
III. Drug Classification Systems
References

3. Measurement and Expression of Drug Effects
I. Introduction
II. In Vitro Experiments
III. Ex Vivo Experiments
IV. In Vivo Experiments
References

4. Molecular Drug Targets
I. Introduction
II. Enzymes as Drug Targets
III. Membrane Transporters as Drug Targets
IV. Voltage-Gated Ion Channels as Drug Targets
V. Non-Selective Cation Channels as Drug Targets
VI. Direct Ligand-Gated Ion Channels (Receptors with Intrinsic Ion Channel)
VII. Receptors with Intrinsic Enzyme Activity
VIII. Receptors Coupled to Various Cytosolic Proteins
IX. G-Protein-Coupled Receptors
X. Nuclear Receptors As Drug Targets
References

5. Drug Targets, Target Identification, Validation and Screening
I. Introduction
II. Improving the Resolution of Disease Etiology
III. Biopharmaceutical Therapies
IV. Drug Target Identification
V. Hit-to-Lead
VI. Clinical Biomarkers
VII. Conclusions
References

Part II Lead Compound Discovery Strategies
6. 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. Conclusion
References

7. High-Throughput Screening and Drug Discovery
I. Introduction
II. Historical Background
III. From Screen to Lead
IV. Examples of Drugs Derived from Screening Leads
V. Practical Application, Recent Example
VI. Conclusion
References

8. 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 Analogs as Drugs
V. Future Directions in Natural Products as Drugs and Drug Design Templates
VI. Summary
References

9. Biology Oriented Synthesis and Diversity Oriented Synthesis in Compound Collection Development
I. Introduction
II. Diversity Oriented Synthesis
III. Biology Oriented Synthesis
IV. Conclusion and Outlook
References

10. In Silico Screening: Hit Finding from Database Mining
I. Introduction
II. Representation of Chemical Structures
III. Data Mining Methods
IV. Database Searches
V. Applications
VI. Conclusion and Future Directions
References

11. Fragment-Based Drug Discovery
I. Ligand-Protein Interactions: First Principles
II. Status of Late 1990s Drug Discovery in the Pharmaceutical Industry
III. What is FBDD?
IV. Creation and Analysis of FBDD Libraries
V. Nuclear Magnetic Resonance
VI. X-ray Crystallography
VII. Other Biophysical and Biochemical Screening Methods
VIII. Methods for Fragment Hit Follow-Up
IX. Trends for the Future
References

12. Lead-Likeness and Drug-Likeness
I. Introduction
II. Assessing " Drug-Likeness
III. Selecting Better Leads: " Lead-Likeness
IV. Conclusion
References

13. 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. Chemical Software Programs
XII. Analysis
XIII. Chemical Publications
XIV. Patent Information
XV. Toxicology
XVI. Metasites and Technology Service Provider Databases

Part III Primary Exploration of Structure-Activity Relationships
14. Molecular Variations in Homologous Series: Vinylogues and Benzologues
I. Homologous Series
II. Vinylogues and Benzologues
References

15. 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 Isosters
References

16. Ring Transformations
I. Introduction
II. Analogical Approaches
III. Disjunctive Approaches
IV. Conjunctive Approaches
V. Conclusion
References

17. Conformational Restriction and/or Steric Hindrance in Medicinal Chemistry
I. Introduction
II. Case studies
III. Summary and Outlook
References

18. Homo and Heterodimer Ligands the Twin Drug Approach
I. Introduction
II. Homodimer and Symmetrical Ligands
III. Heterodimer and Dual Acting Ligands
IV. Binding Mode Analysis of Identical and Non-identical Twin Drugs
V. Conclusion
References

19. Application Strategies for the Primary Structure-Activity Relationship Exploration
I. Introduction
II. Preliminary Considerations
III. Hit Optimization Strategies
IV. Application Rules
References

Part IV Substituents and Functions: Qualitative and Quantitative Aspects of Structure-Activity Relationships
20. 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

21. 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

22. Compound Properties and Drug Quality
I. Introduction
II. Combinatorial Libraries
III. Chemistry Control of Intestinal Permeability
IV. Chemistry Control of Aqueous Solubility
V. In Vitro Potency and Chemistry Control
VI. Metabolic stability
VII. Acceptable Solubility Guidelines for Permeability Screens
References

23. Quantitative Approaches to Structure-Activity Relationships
I. Introduction to QSAR
II. Brief History and Outlook
III. QSAR Methodology
IV. Practical Applications
References

Part V Spatial Organization, Receptor Mapping and Molecular Modeling
24. Overview: The Search for Biologically Useful Chemical Space
I. Introduction
II. How Big is Chemical Space?
III. Biological Space is Extremely Small
IV. Limited Biological Space as an Effective Biological Strategy
References

25. Pharmacological Space
I. What is Pharmacological Space?
II. Chemical Space
III. Target Space
VI. Conclusions
References

26. Optical Isomerism in Drugs
I. Introduction
II. Experimental Facts and Their Interpretation
III. Optical Isomerism and Pharmacodynamic Aspects
IV. Optical Isomerism and Pharmacokinetic Effects
V. Practical Considerations
References

27. Multi-Target Drugs: Strategies and Challenges for Medicinal Chemists
I. Introduction
II. Strategies for Lead Generation
III. Main Areas of Focus in DML Discovery (1990-2005)
IV. Optimization of the Activ

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.