The Practice of Medicinal Chemistry

The Practice of Medicinal Chemistry, 3rd Edition

The Practice of Medicinal Chemistry, 3rd Edition,Camille Wermuth,ISBN9780123741943

C Wermuth   

Academic Press




276 X 216

Nicknamed "The Bible" by medicinal chemists shortly after the first edition published in 1996

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Key Features

* Focus on chemoinformatics and drug discovery
* Enhanced pedagogical features
* New chapters including:
- Drug absorption and transport
- Multi-target drugs
* Updates on hot new areas:
NEW! Drug discovery and the latest techniques
NEW! How potential drugs can move through the drug discovery/ development phases more quickly
NEW! Chemoinformatics


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.


Pharmaceutical researchers in drug discovery, chemists

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. Besides about 300 scientific papers and about 60 patents, Professor Wermuth is co-author or editor of several books including; Pharmacologie Moléculaire, Masson & Cie, Paris; Médicaments Organiques de Synthèse, Masson & Cie, Paris; Medicinal Chemistry for the 21st Century, Bl

Affiliations and Expertise

Prestwick Chemical, Illkirch, France

The Practice of Medicinal Chemistry, 3rd Edition

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 Activity Profile and Wider Selectivity V. The Physicochemical Challenge VI. Summary References 28. Pharmacophore Identification and Pseudo-Receptor Modeling I. Introduction II. Methodology III. Advanced approaches IV. Application study V. Conclusions References 29. 3D Quantitative Structure-Property Relationships I. Introduction II. 3D QSAR Workflow III. 3D QSAR: Conformation Analysis and Molecular Superimposition IV. Calculation of 3D Molecular Field Descriptors V. Statistical Tools VI. Alignment Independent 3D QSAR Techniques VII. Validation Of 3D QSAR Models VIII. Applications IX. Conclusions and Future Directions References 30. Protein Crystallography and Drug Discovery I. Presentation II. Historical Background III. Examples IV. Basic Principles and Methods of Protein Crystallography V. Practical Applications References Part VI Chemical Modifications Influencing the Pharmacokinetic Properties 31. 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 Bibliography 32. Biotransformation Reactions and their Enzymes I. Introduction II. Functionalization Reactions III. Conjugation Reactions IV. Biological Factors Influencing Drug Metabolism V. Concluding Remarks References 33. Biotransformations Leading to Toxic Metabolites: Chemical Aspects I. Historical Background II. Introduction III. Reactions Involved in the Bioactivation Process IV. Examples of Metabolic Conversions Leading to Toxic Metabolites V. Conclusion References 34. 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 35. Strategies for Enhancing Oral Bioavailability and Brain Penetration I. Introduction II. Enhancing Oral Bioavailability III. Enhancing Brain Penetration IV. Conclusion References 36. Designing Prodrugs and Bioprecursors I. Introduction II. The Different Kinds of Prodrugs III. Carrier Prodrugs: Application Examples IV. Particular Aspects of Carrier Prodrug Design V. Bioprecursor Prodrugs: Application Examples VI. Discussion VII. Difficulties and Limitations VIII. Conclusion References Part VII Pharmaceutical and Chemical Means to Solubility and Formulation Problems 37. Preparation of Water-Soluble Compounds through Salt Formation I. Introduction II. The Solubility of Compounds in Water III. Acids and Bases Used in Salt Formation IV. Early salt formation studies V. Comparison of Different Crystalline Salts VI. Implications of Salt Selection on Drug Dosage Forms VII. Conclusion References 38. 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. Non-ionizable Side Chains VI. Concluding Remarks References 39. Drug Solubilization with Organic Solvents, or Using Micellar Solutions or Other Colloidal Dispersed Systems I. Introduction II. Factors Controlling Solubility and Absorption III . Water-cosolvent systems IV. Solubilization Mediated by Surfactants V. Solubilization by Lipid Vehicles VI. Nanoparticles and Other Nanocolloidal Technologies VII. Drug Delivery and Clearance Mechanisms of Nanocolloids VIII. Drug Delivery and Accumulation Using Colloidal Systems for the Treatment of Cancer IX. Modification of Drug Toxicity by Nanocolloidal Drug Delivery Systems References 40. Improvement of Drug Properties by Cyclodextrins I. Introduction II. Pharmaceutically Useful CyDs III. Improvement of Drug Properties IV. CyD-Based Site-Specific Drug Delivery V. Conclusion References 41. Chemical and Physicochemical Approaches to Solve Formulation Problems I. Introduction II. Increasing Chemical Stability III. Improved Formulation of Peptides and Proteins IV. Dealing with Mesomorphic Crystalline Forms V. Increasing the Melting Point VI. Gastrointestinal Irritability and Painful Injections VII. Suppressing Undesirable Organoleptic Properties References Part VIII Development of New Drugs: Legal and Economic Aspects 42. Discover a Drug Substance, Formulate and Develop It to a Product I. Introduction II. Discover the Drug Substance III. Defi ning Experimental Formulations, The Creative Phase IV. Pharmaceutical Development in Industry V. Fixing The Quality And Develop The Product in A Regulated Environment References 43. Drug Nomenclature I. Introduction II. Trade Names and Nonproprietary Names III. Drug Nomenclature IV. Use and Protection of Nonproprietary Names V. Summary References Annex 44. Legal Aspects of Product Protection: What a Medicinal Chemist Should Know about Patent Protection I. Introduction II. Definition of A Patent - Patent Rights III. Kind of Inventions IV. Subjects of Patents: Basic and Formal Requirements for Filing a Patent V. Lifetime of Patents VI. Ownership of Patents VII. Infringement of a Patent VIII. Patents as a Source of Information IX. Patenting in the Pharmaceutical Industries X. Conclusion References 45. The Consumption and Production of Pharmaceuticals I. “ Important ” Drugs II. Sources of Drugs III. Manufacture of Drugs IV. Social and Economic Factors V. The Future of the Pharmaceutical Industry References Index

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