The Practice of Medicinal Chemistry

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.

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