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Drug Discovery and Development, Volume 1: Drug Discovery

Drug Discovery and Development, Volume 1: Drug Discovery

Mukund S. Chorghade (Editor)

ISBN: 978-0-471-78010-6

Jul 2006

476 pages


This two volume set provides a comprehensive account of the entire sequence of operations involved in discovering a drug through the actual delivery of the drug to clinicians and medical practitioners.
  • Includes case studies of the discovery of erythromycin analogs (antibiotics), Tagamet, and Ultiva (remifentanil)
  • Discusses the discovery of agents for the treatment and management of bacterial infections, Parkinson's disease, psoriasis, ulcers and stomach pain, atopic dermatitis, asthma, and cancer
  • Contains chapters on combinatorial chemistry, molecular biology-based drug discovery, genomics, and chemogenomics

The first volume of this set thoroughly describes conceptualizing a drug, creating a library of candidates for testing, screening those candidates for in vitro and in vivo activity, conducting and analyzing the results of clinical trials, and revising the drug as necessary.



1. From Patent to Prescription: Paving the Perilous Path to Profit (Richard J. Pariza).

1.1 Introduction.

1.2 A Simple Solution to a Complex Problem.

1.3 An Intriguing Patent Problem.

1.4 Another Structural Insight.


2. Medicinal Chemistry in the New Millennium: A Glance into the Future (Paul W. Erhardt).

2.1 Introduction.

2.2 Practice of Medicinal Chemistry.

2.2.1 Emergence as a Formalized Discipline.

2.2.2 Early Developments.

2.2.3 Present Status.

2.2.4 Examples Involving Site-Directed Mutagenesis.

2.2.5 Latest Trends.

2.3 Evolving Drug Discovery and Development Process.

2.3.1 Working Defi nition for Medicinal Chemistry.

2.3.2 Immediate- and Long-Term Roles for Medicinal Chemistry.

2.4 Pursuing Efficacy.

2.4.1 Gathering Positive, Neutral, and Negative SARs During HTS.

2.4.2 Example Involving Multidrug Resistance of Anticancer Agents.

2.4.3 Compound Libraries: Example of Working with Nature to Enhance Molecular Diversity.

2.5 Assessing and Handling Molecular Conformation.

2.5.1 Chemoinformatics.

2.5.2 Obtaining Chemically Correct 3D Structures.

2.5.3 Infl uence of Biological Environments: Example Involving Drug Metabolism.

2.5.4 Dynamic Energy Relationships: Example Involving a Small Ring System.

2.5.5 Druglike Properties and Privileged Structures.

2.5.6 Tiered Structural Information and Searching Paradigms.

2.6 ADMET Considerations.

2.6.1 Assuring Absorption.

2.6.2 Directing Distribution.

2.6.3 Herbal Remedies: Example of Working with Nature to Discover

ADMET-Related Synergies, 59

2.6.4 Brute Force HTS to Uncover Multicomponent Synergies.

2.6.5 Controlling Metabolism: Example Involving a Soft Drug Strategy.

2.6.6 Optimizing Excretion.

2.6.7 Avoiding Toxicity.

2.6.8 Weighting Decision Criteria from Effi cacy and ADMET SAR.

2.7 Process Chemistry Considerations.

2.7.1 Cost and Green Chemistry.

2.7.2 Defi ning Stereochemistry: Example Involving Benzylamine Chiral Auxiliary Synthetic Reagents.

2.8 Analytical Chemistry/X-ray Diffraction.

2.8.1 Latest Trends.

2.8.2 Examples Involving Dopamine Receptors, c-AMP Phosphodiesterase Enzymes, and the Dynamics of Protein Folding.

2.9 Summary.

2.9.1 General Points.

2.9.2 Attributes of Drug Discovery Libraries, Compound Hits, and Lead Compounds.

2.9.3 Formalized Instruction of Medicinal Chemistry.

2.9.4 Intellectual Property Considerations.

2.9.5 Knowledge Versus Diversity Paradox.


References and Notes.

3. Contemporary Drug Discovery (Lester A. Mitscher and Apurba Dutta).

3.1 Introduction.

3.1.1 Getting Started.

3.2 Characteristics of a Suitable Lead Substance.

3.2.1 Potency and Selectivity.

3.2.2 Structure–Activity Relationships.

3.2.3 Toxicity.

3.2.4 Changing Appellation of the Best in Series: Analog Attrition.

3.3 Some Criteria That a Hit Must Satisfy to Become a Drug.

3.3.1 Level of Potency.

3.3.2 Comparison of Potency and Efficacy.

3.3.3 Druglike Character.

3.3.4 Effi cacy Following Oral Administration.

3.3.5 Lipinski Rules for Oral Absorption.

3.3.6 Injectable Medications.

3.3.7 Distribution.

3.3.8 Serum Protein Binding.

3.3.9 Metabolism.

3.3.10 Distribution.

3.3.11 Excretion.

3.3.12 Patenting.

3.3.13 Pharmaceutical Properties.

3.3.14 Idiosyncratic Problems.

3.3.15 Summary.

3.4 Example of Drug Development That Illustrates Many of the Aforementioned Considerations.

3.4.1 Control of Blood Pressure with Drugs.

3.4.2 Historical Background.

3.4.3 Finding a Starting Point: A Clue from Nature.

3.4.4 Renin–Angiotensin–Aldosterone System.

3.4.5 Attempts to Inhibit Renin.

3.4.6 Attempts to Inhibit Angiotensin-Converting Enzyme.

3.4.7 Peptides Make Poor Orally Active Drugs.

3.4.8 Analoging Studies of Pit Viper–Inspired Peptides.

3.4.9 Peptidomimetics.

3.4.10 Adaptation to Inhibition of ACE.

3.4.11 Success Inspires Competition.

3.4.12 Taking a Different Approach.

3.4.13 Analoging to Enhance Absorption.

3.4.14 Clinical SAR.

3.4.15 More Recent Work.

3.4.16 Résumé.

3.5 Conclusions.

Additional Reading.

4. Combinatorial Chemistry in the Drug Discovery Process (Ian Hughes).

4.1 Introduction.

4.1.1 The Birth of Combinatorial Chemistry.

4.1.2 Development of Screening Strategies for Libraries.

4.1.3 From Peptides to Small Molecule Synthesis.

4.1.4 Beyond Solid-Phase Chemistry.

4.2 The Role of Combinatorial Chemistry in Drug Discovery.

4.3 Designing Combinatorial Libraries.

4.3.1 Describing and Measuring Diversity.

4.3.2 A More Focused Approach.

4.4 Tools for Synthesis of Combinatorial Libraries.

4.4.1 Nonautomated Tools.

4.4.2 Mix-and-Sort Systems.

4.4.3 Automated Synthesizers.

4.4.4 Postsynthesis Processing.

4.5 Managing the Combinatorial Process.

4.5.1 Specifi cation of Combinatorial Libraries.

4.5.2 Controlling the Automated Workfl ow.

4.6 From Specialist Discipline to Standard Tool.

4.7 Application of Combinatorial Chemistry in Drug Discovery.

4.7.1 Case History 1.

4.7.2 Case History 2.

4.7.3 Case History 3.

4.7.4 Case History 4.

4.8 The Future of Combinatorial Chemistry.

4.8.1 Dynamic Combinatorial Libraries.

4.8.2 Miniaturization.

4.9 Conclusions.


5. Parallel Solution-Phase Synthesis (Norton P. Peet and Hwa-Ok Kim).

5.1 Introduction.

5.2 Ahead of Our Time.

5.3 Recent Reports of Parallel Solution-Phase Synthesis.

5.4 Solid Supported Reagents, Scavengers, and Catalysts.

5.5 The Future.


6. Timing of Analog Research in Medicinal Chemistry (János Fischer and Anikó Gere).

6.1 Introduction.

6.2 Early Phase Analogs.

6.2.1 ACE Inhibitors.

6.2.2 AT1 Antagonists.

6.2.3 Proton Pump Inhibitors.

6.2.4 Insulin Sensitizers: Glitazones.

6.2.5 HMG-CoA Reductase Inhibitors.

6.2.6 Antimigraine Drugs.

6.3 Drug Analogs.

6.3.1 Metoclopramide Analogs.

6.3.2 Azatadine Analogs.

6.3.3 Miconazole Analogs.

6.3.4 Nifedipine Analogs.

6.3.5 Propranolol Analogs.

6.3.6 Clodronate Analogs.

6.4 Summary.


References and Notes.

7. Possible Alternatives to High-Throughput Screening (Camille G. Wermuth).

7.1 Introduction.

7.2 Analog Design.

7.2.1 Defi nitions.

7.2.2 Pharmacophere-Based Analog Design: Scaffold Hopping or Scaffold Morphing.

7.2.3 Natural Compounds as Models.

7.2.4 Emergence of New Activities.

7.3 Physiopathological Hypotheses.

7.3.1 Discovery of Levodopa.

7.3.2 H2-Receptor Antagonists.

7.3.3 Rimonabant and Obesity.

7.4 Contributions from Clinical Investigations.

7.5 New Leads from Old Drugs: The SOSA Approach.

7.5.1 Rationale.

7.5.2 Examples.

7.5.3 Discussion.

7.6 Conclusion.


8. Proteomics and Drug Discovery (Susan Dana Jones and Peter G. Warren).

8.1 Introduction.

8.2 Drug Discovery Process.

8.2.1 Process Overview.

8.2.2 Motivation for Improvement.

8.3 High-Throughput Screening Approaches to Drug Discovery.

8.4 Emerging Technologies and Approaches: Scale and Speed.

8.5 Genomics.

8.6 Proteomics.

8.6.1 Functional Areas of Proteomics.

8.6.2 Fractionation and Purification.

8.6.3 Identification.

8.6.4 Quantitation.

8.6.5 Characterization.

8.7 Protein Chip Technology.

8.7.1 Issues Addressed.

8.7.2 Current State of the Technology.

8.8 Proteomics Data Analysis: Computational Biology and Bioinformatics.

8.9 Proteomics and Drug Discovery.

8.9.1 Target Identification.

8.9.2 Target Validation.

8.9.3 Screening for Hits.

8.9.4 Lead Optimization.

8.9.5 Pharmacology and ADME-Tox.

8.9.6 Clinical Trials: Biomarkers and Pharmacogenomics.

8.9.7 Case Study.

8.10 Conclusions.



Appendix: Public-Domain Software Tools and Databases.

9. Using Drug Metabolism Databases During Drug Design and Development (Paul W. Erhardt).

9.1 Introduction.

9.2 Historical Perspective.

9.3 Present Status.

9.4 Future Prospects.

9.5 Summary.

References and Notes.

10. Discovery of the Antiulcer Drug Tagamet (C. Robin Ganellin).

10.1 Historical Background.

10.1.1 Prologue.

10.1.2 Pharmacological Receptors.

10.1.3 Peptic Ulcer Disease.

10.1.4 Search for New Antiulcer Drugs.

10.2 Search for an H2-Receptor Histamine Antagonist.

10.2.1 Histamine Receptors.

10.2.2 Biological Approach to a Histamine Antagonist at Non-H1 Receptors.

10.2.3 Chemical Approach to an Antagonist: Generating a Lead.

10.2.4 Lead Optimization.

10.2.5 Validating the Research Program.

10.3 Development of a Clinical Candidate Drug.

10.3.1 Dynamic Structure–Activity Analysis.

10.3.2 Imidazole Tautomerism and Sulfur Methylene Isosterism.

10.3.3 Isosteres of Thiourea and the Discovery of Cimetidine.

10.3.4 Cimetidine: A Breakthrough in the Treatment of Peptic Ulcer Disease.

10.4 Summary and Further Observations.


11. Discovery of Potent Nonpeptide Vasopressin Receptor Antagonists (Bruce E. Maryanoff).

11.1 Introduction.

11.2 Genesis of the Vasopressin Receptor Antagonist Project.

11.3 Vasopressin, Its Receptors, and Disease.

11.4 The Game Plan.

11.5 Novel Chemotypes: Variations on a Theme.

11.5.1 Azepinoindoles.

11.5.2 Bridged Bicyclic Derivatives.

11.5.3 Thiazino-, Oxazino-, and Pyrazinobenzodiazepines.

11.6 Epilogue.


References and Notes.

12. Discovery and Development of the Ultrashort-Acting Analgesic Remifentanil (Paul L. Feldman).

12.1 Introduction.

12.2 Discovery of Remifentanil.

12.3 Chemical Development of Remifentanil.

12.4 Human Clinical Trials with Remifentanil.



13. Discovery and Development of Nevirapine (Karl Grozinger, John Proudfoot, and Karl Hargrave).

13.1 Introduction.

13.2 Lead Discovery and Optimization.

13.3 Chemical Development and Process Research.

13.4 Mechanism of Action.

13.5 Clinical Studies.



14. Applications of Nuclear Imaging in Drug Discovery and Development (John W. Babich and William C. Eckelman).

14.1 Introduction.

14.1.1 Process and Challenges of Drug Development.

14.1.2 Role and Contribution of Position Emission Tomography.

14.2 Principles and Evolution of Technology.

14.2.1 Introduction to PET Principles.

14.2.2 Suitable Targets.

14.2.3 Suitable Animal Models.

14.3 Role in Drug Discovery.

14.3.1 Target Validation and Drug Design.

14.3.2 Preclinical Studies.

14.3.3 Clinical Studies.

14.4 Summary and Outlook.


15. Polymeric Sequestrants as Nonabsorbed Human Therapeutics (Pradeep K. Dhal, Chad C. Huval, and S. Randall Holmes-Farley).

15.1 Introduction.

15.2 Polymers as Specifi c Molecular Sequestrants.

15.3 Sequestration of Inorganic Ions in the GI Tract.

15.4 Polymeric Potassium Sequestrants: A Nonabsorbed Therapy for Hyperkalemia.

15.5 Polymeric Drugs for Chronic Renal Failure.

15.6 Polymeric Iron Sequestrants for the Treatment of Iron Overload Disorders.

15.7 Sequestration of Bile Acids: Polymers as Cholesterol-Lowering Agents.

15.8 Sequestration of Pathogens: Polymeric Anti-infective Agents.

15.9 Sequestration of Toxins.

15.10 Polymeric Antimicrobial Agents.

15.11 Conclusions and Outlook.


16. Botanical Immunomodulators and Chemoprotectants in Cancer Therapy (Bhushan Patwardhan, Sham Diwanay, and Manish Gautam).

16.1 Introduction.

16.2 Immunomodulation.

16.3 Ethnopharmacology and Botanical Immunomodulators.

16.4 Adaptogens or Adjustive Medicine.

16.4.1 Botanicals with Adaptogenic Activity.

16.4.2 Rasayana Botanicals as Adaptogens.

16.5 Chemoprotection.

16.5.1 Drug Targets and Current Trends.

16.5.2 Chemoprotectants for Antimetabolites.

16.5.3 Thiol-Based Chemoprotectants for Cisplatin and Oxazophosphorine-Based Alkylating Agents.

16.5.4 Chemoprotectants for Anthracyclines.

16.5.5 Botanical Immunomodulators as Chemoprotectants.

16.6 Radioprotection.

16.6.1 Radioprotectants from Botanicals.

16.6.2 Botanical Immunomodulators as Antitumor Agents.

16.7 Conclusions.



""...provides a nice survey of most of the key topics facing discovery houses today."" (Doody's Health Services)

""This reasonably priced book is well-written and produced. It has a useful 32-page index, and it may be considered for acquisition by individuals and libraries."" (Journal of Medicinial Chemistry, October 5, 2006)