The Practice of Medicinal Chemistry

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

Prestwick Chemical, Illkirch, 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

Prestwick Chemical, Illkirch, France

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