Drug Discovery and Development, Volume 1

Name: Drug Discovery and Development, Volume 1 | Drug Discovery
Brand: Wiley
Price: 141.99 EUR
Availability: OnlineOnly

Drug Discovery

Mukund S. Chorghade(Herausgeber*in)

Wiley (Verlag)

Erschienen am 24. Juli 2006

456 Seiten

E-Book

PDF mit Adobe-DRM

Systemvoraussetzungen

978-0-471-78009-0 (ISBN)

141,99 €inkl. 7% MwSt.

Systemvoraussetzungen

für PDF mit Adobe-DRM

E-Book Einzellizenz

Als Download verfügbar

Beschreibung

Weitere Details

Weitere Ausgaben

Person

Inhalt

Intro
DRUG DISCOVERY AND DEVELOPMENT
CONTENTS
Contributors
Preface
1 From Patent to Prescription: Paving the Perilous Path to Profit
1.1 Introduction
1.2 A Simple Solution to a Complex Problem
1.3 An Intriguing Patent Problem
1.4 Another Structural Insight
References
2 Medicinal Chemistry in the New Millennium: A Glance into the Future
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 Definition 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 Influence 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
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 Efficacy and ADMET SAR
2.7 Process Chemistry Considerations
2.7.1 Cost and Green Chemistry
2.7.2 Defining 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
Acknowledgments
References and Notes
3 Contemporary Drug Discovery
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 Efficacy 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
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 Specification of Combinatorial Libraries
4.5.2 Controlling the Automated Workflow
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
References
5 Parallel Solution-Phase Synthesis
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
References
6 Timing of Analog Research in Medicinal Chemistry
6.1 Introduction
6.2 Early Phase Analogs
6.2.1 ACE Inhibitors
6.2.2 AT(1) 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
Acknowledgments
References and Notes
7 Possible Alternatives to High-Throughput Screening
7.1 Introduction
7.2 Analog Design
7.2.1 Definitions
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 H(2)-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
References
8 Proteomics and Drug Discovery
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
Acknowledgments
References
Appendix: Public-Domain Software Tools and Databases
9 Using Drug Metabolism Databases During Drug Design and Development
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
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 H(2)-Receptor Histamine Antagonist
10.2.1 Histamine Receptors
10.2.2 Biological Approach to a Histamine Antagonist at Non-H(1) 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
References
11 Discovery of Potent Nonpeptide Vasopressin Receptor Antagonists
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
Acknowledgments
References and Notes
12 Discovery and Development of the Ultrashort-Acting Analgesic Remifentanil
12.1 Introduction
12.2 Discovery of Remifentanil
12.3 Chemical Development of Remifentanil
12.4 Human Clinical Trials with Remifentanil
Acknowledgments
References
13 Discovery and Development of Nevirapine
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
Acknowledgments
References
14 Applications of Nuclear Imaging in Drug Discovery and Development
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
References
15 Polymeric Sequestrants as Nonabsorbed Human Therapeutics
15.1 Introduction
15.2 Polymers as Specific 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
References
16 Botanical Immunomodulators and Chemoprotectants in Cancer Therapy
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
References
Index

Inhalt (PDF)

Systemvoraussetzungen

Als PDF speichern Als Link merken