The Practice of Medicinal Chemistry
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The Practice of Medicinal Chemistry

3rd Edition - July 24, 2008

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  • Editors: Camille Wermuth, Camille Wermuth
  • eBook ISBN: 9780080568775

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Description

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.

Key Features

NEW TO THIS EDITION:
* 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

Readership

Pharmaceutical researchers in drug discovery, chemists

Table of Contents

  • 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

Product details

  • No. of pages: 982
  • Language: English
  • Copyright: © Academic Press 2008
  • Published: July 24, 2008
  • Imprint: Academic Press
  • eBook ISBN: 9780080568775

About the Editors

Camille Wermuth

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

Professor of Organic Chemistry and Medicinal Chemistry at the Faculty of Pharmacy, Louis Pasteur University, Strasbourg, France

Camille Wermuth

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

Professor of Organic Chemistry and Medicinal Chemistry at the Faculty of Pharmacy, Louis Pasteur University, Strasbourg, France

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