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.
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
