Drug Discovery and Development, Volume 1 Drug Discovery

by Chorghade, Mukund S.

• ISBN13: 9780471398486
• ISBN10: 0471398489
• Edition: 1st
• Format: Hardcover
• Copyright: 2006-06-16
• Publisher: Wiley-Interscience

Summary

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.

Author Biography

Mukund S. Chorghade, PHD, is President of Chorghade Enterprises, Inc., a firm based in Natick, Massachusetts that provides consultations to major pharmaceutical companieson collaborations with worldwide academic, government, and industrial laboratories; European technology-based companies; process reengineering; and project management of technology transfer.

Table of Contents

Contributors	xiii
Preface	xv
From Patent to Prescription: Paving the Perilous Path to Profit	1	(16)
Richard J. Pariza
Introduction	1	(2)
A Simple Solution to a Complex Problem	3	(5)
An Intriguing Patent Problem	8	(2)
Another Structural Insight	10	(7)
References	15	(2)
Medicinal Chemistry in the New Millennium: A Glance into the Future	17	(86)
Paul W. Erhardt
Introduction	17	(2)
Practice of Medicinal Chemistry	19	(16)
Emergence as a Formalized Discipline	19	(4)
Early Developments	23	(3)
Present Status	26	(1)
Examples Involving Site-Directed Mutagenesis	27	(4)
Latest Trends	31	(4)
Evolving Drug Discovery and Development Process	35	(5)
Working Definition for Medicinal Chemistry	35	(1)
Immediate- and Long-Term Roles for Medicinal Chemistry	36	(4)
Pursuing Efficacy	40	(6)
Gathering Positive, Neutral, and Negative SARs During HTS	41	(1)
Example Involving Multidrug Resistance of Anticancer Agents	42	(3)
Compound Libraries: Example of Working with Nature to Enhance Molecular Diversity	45	(1)
Assessing and Handling Molecular Conformation	46	(11)
Chemoinformatics	46	(3)
Obtaining Chemically Correct 3D Structures	49	(1)
Influence of Biological Environments: Example Involving Drug Metabolism	50	(2)
Dynamic Energy Relationships: Example Involving a Small Ring System	52	(2)
Druglike Properties and Privileged Structures	54	(1)
Tiered Structural Information and Searching Paradigms	55	(2)
ADMET Considerations	57	(13)
Assuring Absorption	57	(1)
Directing Distribution	58	(1)
Herbal Remedies: Example of Working with Nature to Discover ADMET-Related Synergies	59	(3)
Brute Force HTS to Uncover Multicomponent Synergies	62	(1)
Controlling Metabolism: Example Involving a Soft Drug Strategy	63	(2)
Optimizing Excretion	65	(1)
Avoiding Toxicity	65	(2)
Weighting Decision Criteria from Efficacy and ADMET SAR	67	(3)
Process Chemistry Considerations	70	(4)
Cost and Green Chemistry	70	(1)
Defining Stereochemistry: Example Involving Benzylamine Chiral Auxiliary Synthetic Reagents	71	(3)
Analytical Chemistry/X-ray Diffraction	74	(4)
Latest Trends	74	(1)
Examples Involving Dopamine Receptors, c-AMP Phosphodiesterase Enzymes, and the Dynamics of Protein Folding	75	(3)
Summary	78	(25)
General Points	78	(3)
Attributes of Drug Discovery Libraries, Compound Hits, and Lead Compounds	81	(1)
Formalized Instruction of Medicinal Chemistry	81	(2)
Intellectual Property Considerations	83	(1)
Knowledge Versus Diversity Paradox	84	(1)
Acknowledgments	85	(1)
References and Notes	85	(18)
Contemporary Drug Discovery	103	(26)
Lester A. Mitscher
Apurba Dutta
Introduction	103	(1)
Getting Started	103	(1)
Characteristics of a Suitable Lead Substance	104	(4)
Potency and Selectivity	105	(2)
Structure--Activity Relationships	107	(1)
Toxicity	107	(1)
Changing Appellation of the Best in Series: Analog Attrition	108	(1)
Some Criteria That a Hit Must Satisfy to Become a Drug	108	(8)
Level of Potency	109	(1)
Comparison of Potency and Efficacy	110	(1)
Druglike Character	110	(1)
Efficacy Following Oral Administration	110	(2)
Lipinski Rules for Oral Absorption	112	(1)
Injectable Medications	113	(1)
Distribution	113	(1)
Serum Protein Binding	114	(1)
Metabolism	114	(1)
Distribution	114	(1)
Excretion	115	(1)
Patenting	115	(1)
Pharmaceutical Properties	115	(1)
Idiosyncratic Problems	115	(1)
Summary	115	(1)
Example of Drug Development That Illustrates Many of the Aforementioned Considerations	116	(12)
Control of Blood Pressure with Drugs	116	(1)
Historical Background	116	(1)
Finding a Starting Point: A Clue from Nature	117	(1)
Renin--Angiotensin--Aldosterone System	117	(2)
Attempts to Inhibit Renin	119	(1)
Attempts to Inhibit Angiotensin-Converting Enzyme	119	(1)
Peptides Make Poor Orally Active Drugs	120	(1)
Analoging Studies of Pit Viper--Inspired Peptides	120	(1)
Peptidomimetics	120	(1)
Adaptation to Inhibition of ACE	121	(2)
Success Inspires Competition	123	(1)
Taking a Different Approach	124	(1)
Analoging to Enhance Absorption	124	(2)
Clinical SAR	126	(2)
More Recent Work	128	(1)
Resume	128	(1)
Conclusions	128	(1)
Additional Reading	128	(1)
Combinatorial Chemistry in the Drug Discovery Process	129	(40)
Ian Hughes
Introduction	129	(6)
The Birth of Combinatorial Chemistry	130	(1)
Development of Screening Strategies for Libraries	131	(1)
From Peptides to Small Molecule Synthesis	132	(1)
Beyond Solid-Phase Chemistry	133	(2)
The Role of Combinatorial Chemistry in Drug Discovery	135	(2)
Designing Combinatorial Libraries	137	(4)
Describing and Measuring Diversity	137	(2)
A More Focused Approach	139	(2)
Tools for Synthesis of Combinatorial Libraries	141	(5)
Nonautomated Tools	141	(2)
Mix-and-Sort Systems	143	(1)
Automated Synthesizers	143	(1)
Postsynthesis Processing	144	(2)
Managing the Combinatorial Process	146	(2)
Specification of Combinatorial Libraries	146	(1)
Controlling the Automated Workflow	146	(2)
From Specialist Discipline to Standard Tool	148	(1)
Application of Combinatorial Chemistry in Drug Discovery	149	(5)
Case History 1	150	(1)
Case History 2	150	(1)
Case History 3	151	(1)
Case History 4	152	(2)
The Future of Combinatorial Chemistry	154	(1)
Dynamic Combinatorial Libraries	154	(1)
Miniaturization	154	(1)
Conclusions	155	(14)
References	156	(13)
Parallel Solution-Phase Synthesis	169	(30)
Norton P. Peet
Hwa-Ok Kim
Introduction	169	(1)
Ahead of Our Time	169	(3)
Recent Reports of Parallel Solution-Phase Synthesis	172	(6)
Solid Supported Reagents, Scavengers, and Catalysts	178	(13)
The Future	191	(8)
References	191	(8)
Timing of Analog Research in Medicinal Chemistry	199	(14)
Janos Fischer
Aniko Gere
Introduction	199	(1)
Early Phase Analogs	199	(3)
ACE Inhibitors	199	(1)
AT1 Antagonists	200	(1)
Proton Pump Inhibitors	200	(1)
Insulin Sensitizers: Glitazones	200	(2)
HMG-CoA Reductase Inhibitors	202	(1)
Antimigraine Drugs	202	(1)
Drug Analogs	202	(6)
Metoclopramide Analogs	203	(2)
Azatadine Analogs	205	(1)
Miconazole Analogs	205	(1)
Nifedipine Analogs	206	(1)
Propranolol Analogs	207	(1)
Clodronate Analogs	207	(1)
Summary	208	(5)
Acknowledgments	210	(1)
References and Notes	210	(3)
Possible Alternatives to High-Throughput Screening	213	(20)
Camille G. Wermuth
Introduction	213	(1)
Analog Design	214	(3)
Definitions	214	(1)
Pharmacophere-Based Analog Design: Scaffold Hopping or Scaffold Morphing	215	(1)
Natural Compounds as Models	216	(1)
Emergence of New Activities	216	(1)
Physiopathological Hypotheses	217	(4)
Discovery of Levodopa	217	(2)
H2-Receptor Antagonists	219	(1)
Rimonabant and Obesity	220	(1)
Contributions from Clinical Investigations	221	(2)
New Leads from Old Drugs: The SOSA Approach	223	(5)
Rationale	223	(1)
Examples	223	(3)
Discussion	226	(2)
Conclusion	228	(5)
References	229	(4)
Proteomics and Drug Discovery	233	(40)
Susan Dana Jones
Peter G. Warren
Introduction	233	(1)
Drug Discovery Process	234	(2)
Process Overview	234	(2)
Motivation for Improvement	236	(1)
High-Throughput Screening Approaches to Drug Discovery	236	(1)
Emerging Technologies and Approaches: Scale and Speed	237	(1)
Genomics	237	(1)
Proteomics	238	(10)
Functional Areas of Proteomics	239	(1)
Fractionation and Purification	239	(1)
Identification	240	(2)
Quantitation	242	(1)
Characterization	243	(5)
Protein Chip Technology	248	(5)
Issues Addressed	248	(1)
Current State of the Technology	249	(4)
Proteomics Data Analysis: Computational Biology and Bioinformatics	253	(3)
Proteomics and Drug Discovery	256	(10)
Target Identification	256	(2)
Target Validation	258	(1)
Screening for Hits	259	(2)
Lead Optimization	261	(1)
Pharmacology and ADME-Tox	262	(1)
Clinical Trials: Biomarkers and Pharmacogenomics	263	(2)
Case Study	265	(1)
Conclusions	266	(7)
Acknowledgments	267	(1)
References	267	(2)
Appendix: Public-Domain Software Tools and Databases	269	(4)
Using Drug Metabolism Databases During Drug Design and Development	273	(22)
Paul W. Erhardt
Introduction	273	(2)
Historical Perspective	275	(1)
Present Status	276	(4)
Future Prospects	280	(7)
Summary	287	(8)
References and Notes	288	(7)
Discovery of the Antiulcer Drug Tagamet	295	(18)
C. Robin Ganellin
Historical Background	295	(3)
Prologue	295	(1)
Pharmacological Receptors	296	(1)
Peptic Ulcer Disease	296	(2)
Search for New Antiulcer Drugs	298	(1)
Search for an H2-Receptor Histamine Antagonist	298	(7)
Histamine Receptors	298	(1)
Biological Approach to a Histamine Antagonist at Non-H1 Receptors	299	(1)
Chemical Approach to an Antagonist: Generating a Lead	300	(1)
Lead Optimization	301	(2)
Validating the Research Program	303	(2)
Development of a Clinical Candidate Drug	305	(4)
Dynamic Structure--Activity Analysis	305	(1)
Imidazole Tautomerism and Sulfur Methylene Isosterism	306	(1)
Isosteres of Thiourea and the Discovery of Cimetidine	307	(1)
Cimetidine: A Breakthrough in the Treatment of Peptic Ulcer Disease	308	(1)
Summary and Further Observations	309	(4)
References	310	(3)
Discovery of Potent Nonpeptide Vasopressin Receptor Antagonists	313	(26)
Bruce E. Maryanoff
Introduction	313	(2)
Genesis of the Vasopressin Receptor Antagonist Project	315	(1)
Vasopressin, Its Receptors, and Disease	315	(2)
The Game Plan	317	(2)
Novel Chemotypes: Variations on a Theme	319	(13)
Azepinoindoles	319	(3)
Bridged Bicyclic Derivatives	322	(2)
Thiazino-, Oxazino-, and Pyrazinobenzodiazepines	324	(8)
Epilogue	332	(7)
Acknowledgments	333	(1)
References and Notes	333	(6)
Discovery and Development of the Ultrashort-Acting Analgesic Remifentanil	339	(14)
Paul L. Feldman
Introduction	339	(1)
Discovery of Remifentanil	340	(4)
Chemical Development of Remifentanil	344	(5)
Human Clinical Trials with Remifentanil	349	(4)
Acknowledgments	350	(1)
References	350	(3)
Discovery and Development of Nevirapine	353	(12)
Karl Grozinger
John Proudfoot
Karl Hargrave
Introduction	353	(2)
Lead Discovery and Optimization	355	(2)
Chemical Development and Process Research	357	(3)
Mechanism of Action	360	(1)
Clinical Studies	361	(4)
Acknowledgments	362	(1)
References	362	(3)
Applications of Nuclear Imaging in Drug Discovery and Development	365	(18)
John W. Babich
William C. Eckelman
Introduction	365	(1)
Process and Challenges of Drug Development	365	(1)
Role and Contribution of Position Emission Tomography	366	(1)
Principles and Evolution of Technology	366	(2)
Introduction to PET Principles	366	(1)
Suitable Targets	367	(1)
Suitable Animal Models	367	(1)
Role in Drug Discovery	368	(8)
Target Validation and Drug Design	368	(3)
Preclinical Studies	371	(2)
Clinical Studies	373	(3)
Summary and Outlook	376	(7)
References	377	(6)
Polymeric Sequestrants as Nonabsorbed Human Therapeutics	383	(22)
Pradeep K. Dhal
Chad C. Huval
S. Randall Holmes-Farley
Introduction	383	(1)
Polymers as Specific Molecular Sequestrants	384	(1)
Sequestration of Inorganic Ions in the GI Tract	385	(1)
Polymeric Potassium Sequestrants: A Nonabsorbed Therapy for Hyperkalemia	385	(1)
Polymeric Drugs for Chronic Renal Failure	386	(3)
Polymeric Iron Sequestrants for the Treatment of Iron Overload Disorders	389	(3)
Sequestration of Bile Acids: Polymers as Cholesterol-Lowering Agents	392	(4)
Sequestration of Pathogens: Polymeric Anti-infective Agents	396	(1)
Sequestration of Toxins	397	(3)
Polymeric Antimicrobial Agents	400	(1)
Conclusions and Outlook	401	(4)
References	402	(3)
Botanical Immunomodulators and Chemoprotectants in Cancer Therapy	405	(20)
Bhushan Patwardhan
Sham Diwanay
Manish Gautam
Introduction	405	(1)
Immunomodulation	406	(1)
Ethnopharmacology and Botanical Immunomodulators	406	(1)
Adaptogens or Adjustive Medicine	407	(2)
Botanicals with Adaptogenic Activity	407	(1)
Rasayana Botanicals as Adaptogens	408	(1)
Chemoprotection	409	(8)
Drug Targets and Current Trends	409	(1)
Chemoprotectants for Antimetabolites	410	(1)
Thiol-Based Chemoprotectants for Cisplatin and Oxazophosphorine-Based Alkylating Agents	411	(3)
Chemoprotectants for Anthracyclines	414	(1)
Botanical Immunomodulators as Chemoprotectants	414	(3)
Radioprotection	417	(2)
Radioprotectants from Botanicals	418	(1)
Botanical Immunomodulators as Antitumor Agents	418	(1)
Conclusions	419	(6)
References	420	(5)
Index	425