The Practice of Medicinal Chemistry

The Practice of Medicinal Chemistry

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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.
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Product details

  • Hardback | 982 pages
  • 214 x 278 x 40mm | 2,181.77g
  • Academic Press Inc
  • San Diego, United States
  • English
  • 3rd edition
  • Approx. 910 illustrations (900 in full color)
  • 0123741947
  • 9780123741943
  • 2,129,966

Review quote

"Having favorably reviewed the first edition, I still highly recommend this third edition to all chemists who are involved in the drug discovery process."
- John L. Neumeyer, Harvard Medical School, in JOURNAL OF MEDICINAL CHEMISTRY from the American Chemical Society
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About Camille Georges 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 Appliqu es 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 Soci t Fran aise de Chimie Th rapeutique, the L on 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.
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Table of contents


Section Editors


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


2. Medicinal Chemistry: Definitions and Objectives, Drug Activity Phases, Drug Classification Systems

I. Definitions and Objectives

II. Drug Activity Phases

III. Drug Classification Systems


3. Measurement and Expression of Drug Effects

I. Introduction

II. In Vitro Experiments

III. Ex Vivo Experiments

IV. In Vivo Experiments


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


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


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


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


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


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


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


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


12. Lead-Likeness and Drug-Likeness

I. Introduction

II. Assessing " Drug-Likeness "

III. Selecting Better Leads: " Lead-Likeness "

IV. Conclusion


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


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


16. Ring Transformations

I. Introduction

II. Analogical Approaches

III. Disjunctive Approaches

IV. Conjunctive Approaches

V. Conclusion


17. Conformational Restriction and/or Steric Hindrance in Medicinal Chemistry

I. Introduction

II. Case studies

III. Summary and Outlook


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


19. Application Strategies for the Primary Structure-Activity Relationship Exploration

I. Introduction

II. Preliminary Considerations

III. Hit Optimization Strategies

IV. Application Rules


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


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


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


23. Quantitative Approaches to Structure-Activity Relationships

I. Introduction to QSAR

II. Brief History and Outlook

III. QSAR Methodology

IV. Practical Applications


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


25. Pharmacological Space

I. What is Pharmacological Space?

II. Chemical Space

III. Target Space

VI. Conclusions


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


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


28. Pharmacophore Identification and Pseudo-Receptor Modeling

I. Introduction

II. Methodology

III. Advanced approaches

IV. Application study

V. Conclusions


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


30. Protein Crystallography and Drug Discovery

I. Presentation

II. Historical Background

III. Examples

IV. Basic Principles and Methods of Protein Crystallography

V. Practical Applications


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


32. Biotransformation Reactions and their Enzymes

I. Introduction

II. Functionalization Reactions

III. Conjugation Reactions

IV. Biological Factors Influencing Drug Metabolism

V. Concluding Remarks


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


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



35. Strategies for Enhancing Oral Bioavailability and Brain Penetration

I. Introduction

II. Enhancing Oral Bioavailability

III. Enhancing Brain Penetration

IV. Conclusion


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


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


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


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


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


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


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


43. Drug Nomenclature

I. Introduction

II. Trade Names and Nonproprietary Names

III. Drug Nomenclature

IV. Use and Protection of Nonproprietary Names

V. Summary



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


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


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Review Text

"A useful, authoritative discussion of the principles and practice of medicinal chemistry... the volume has a useful index, is well produced and is very reasonably priced."
- JOURNAL OF MEDICINAL CHEMISTRY "A useful, authoritative discussion of the principles and practice of medicinal chemistry... the volume has a useful index, is well produced and is very reasonably priced."
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