Drug Discovery and Development Volume 2 penetrates the details of:

• optimizing the synthetic route
• drug manufacturing
• outsourcing
• marketing
• drug coloring
• delivery methods

Contents

From Patent to Prescription: Paving the Perilous Path to Profit

• A Simple Solution to a Complex Problem
• An Intriguing Patent Problem
• Another Structural Insight

Medicinal Chemistry in the New Millennium: A Glance into the Future

• Practice of Medicinal Chemistry
• Emergence as a Formalized Discipline
• Early Developments
• Present Status
• Examples Involving Site-Directed Mutagenesis
• Evolving Drug Discovery and Development Process
• Working Defi nition for Medicinal Chemistry
• Immediate- and Long-Term Roles for Medicinal Chemistry
• Pursuing Efficacy
• Gathering Positive, Neutral, and Negative SARs During HTS
• Example Involving Multidrug Resistance of Anticancer Agents
• Compound Libraries: Example of Working with Nature to Enhance Molecular Diversity
• Assessing and Handling Molecular Conformation
• Chemoinformatics
• Obtaining Chemically Correct 3D Structures
• Infl uence of Biological Environments: Example Involving Drug Metabolism
• Dynamic Energy Relationships: Example Involving a Small Ring System
• Druglike Properties and Privileged Structures
• Tiered Structural Information and Searching Paradigms
• ADMET Considerations
• Assuring Absorption
• Directing Distribution
• Herbal Remedies: Example of Working with Nature to Discover
• Brute Force HTS to Uncover Multicomponent Synergies
• Controlling Metabolism: Example Involving a Soft Drug Strategy
• Optimizing Excretion
• Avoiding Toxicity
• Weighting Decision Criteria from Effi cacy and ADMET SAR
• Process Chemistry Considerations
• Cost and Green Chemistry
• Defi ning Stereochemistry: Example Involving Benzylamine Chiral Auxiliary Synthetic Reagents
• Analytical Chemistry/X-ray Diffraction
• Latest Trends
• Examples Involving Dopamine Receptors, c-AMP Phosphodiesterase Enzymes, and the Dynamics of Protein Folding
• Attributes of Drug Discovery Libraries, Compound Hits, and Lead Compounds
• Formalized Instruction of Medicinal Chemistry
• Intellectual Property Considerations
• Knowledge Versus Diversity Paradox

Contemporary Drug Discovery

• Characteristics of a Suitable Lead Substance
• Potency and Selectivity
• Structure–Activity Relationships
• Toxicity
• Changing Appellation of the Best in Series: Analog Attrition
• Some Criteria That a Hit Must Satisfy to Become a Drug
• Level of Potency
• Comparison of Potency and Efficacy
• Druglike Character
• Effi cacy Following Oral Administration
• Lipinski Rules for Oral Absorption
• Injectable Medications
• Distribution
• Serum Protein Binding
• Metabolism
• Distribution
• Excretion
• Patenting
• Pharmaceutical Properties
• Idiosyncratic Problems
• Example of Drug Development That Illustrates Many of the Aforementioned Considerations
• Control of Blood Pressure with Drugs
• Historical Background
• Finding a Starting Point: A Clue from Nature
• Renin–Angiotensin–Aldosterone System
• Attempts to Inhibit Renin
• Attempts to Inhibit Angiotensin-Converting Enzyme
• Peptides Make Poor Orally Active Drugs
• Analoging Studies of Pit Viper–Inspired Peptides
• Peptidomimetics
• Adaptation to Inhibition of ACE
• Success Inspires Competition
• Taking a Different Approach
• Analoging to Enhance Absorption
• Clinical SAR

Combinatorial Chemistry in the Drug Discovery Process

• The Birth of Combinatorial Chemistry
• Development of Screening Strategies for Libraries
• From Peptides to Small Molecule Synthesis
• Beyond Solid-Phase Chemistry
• The Role of Combinatorial Chemistry in Drug Discovery
• Designing Combinatorial Libraries
• Describing and Measuring Diversity
• A More Focused Approach
• Tools for Synthesis of Combinatorial Libraries
• Nonautomated Tools
• Mix-and-Sort Systems
• Automated Synthesizers
• Postsynthesis Processing
• Managing the Combinatorial Process
• Specifi cation of Combinatorial Libraries
• Controlling the Automated Workflow
• From Specialist Discipline to Standard Tool
• Application of Combinatorial Chemistry in Drug Discovery

Parallel Solution-Phase Synthesis

• Recent Reports of Parallel Solution-Phase Synthesis
• Solid Supported Reagents, Scavengers, and Catalysts

Timing of Analog Research in Medicinal Chemistry

• Early Phase Analogs
• ACE Inhibitors
• AT1 Antagonists
• Proton Pump Inhibitors
• Insulin Sensitizers: Glitazones
• HMG-CoA Reductase Inhibitors
• Antimigraine Drugs
• Drug Analogs
• Metoclopramide Analogs
• Azatadine Analogs
• Miconazole Analogs
• Nifedipine Analogs
• Propranolol Analogs
• Clodronate Analogs

Possible Alternatives to High-Throughput Screening

• Analog Design
• Pharmacophere-Based Analog Design: Scaffold Hopping or Scaffold Morphing
• Natural Compounds as Models
• Emergence of New Activities
• Physiopathological Hypotheses
• Discovery of Levodopa
• H2-Receptor Antagonists
• Rimonabant and Obesity
• Contributions from Clinical Investigations
• New Leads from Old Drugs: The SOSA Approach

Proteomics and Drug Discovery

• Drug Discovery Process
• Motivation for Improvement
• High-Throughput Screening Approaches to Drug Discovery
• Emerging Technologies and Approaches: Scale and Speed
• Genomics
• Proteomics
• Functional Areas of Proteomics
• Fractionation and Purification
• Identification
• Quantitation
• Characterization
• Protein Chip Technology
• Issues Addressed
• Current State of the Technology
• Proteomics Data Analysis: Computational Biology and Bioinformatics
• Proteomics and Drug Discovery
• Target Identification
• Target Validation
• Screening for Hits
• Lead Optimization
• Pharmacology and ADME-Tox
• Clinical Trials: Biomarkers and Pharmacogenomics

Using Drug Metabolism Databases During Drug Design and Development

Discovery of the Antiulcer Drug Tagamet

• Pharmacological Receptors
• Peptic Ulcer Disease
• Search for New Antiulcer Drugs
• Search for an H2-Receptor Histamine Antagonist
• Histamine Receptors
• Biological Approach to a Histamine Antagonist at Non-H1 Receptors
• Chemical Approach to an Antagonist: Generating a Lead
• Lead Optimization
• Validating the Research Program
• Development of a Clinical Candidate Drug
• Dynamic Structure–Activity Analysis
• Imidazole Tautomerism and Sulfur Methylene Isosterism
• Isosteres of Thiourea and the Discovery of Cimetidine
• Cimetidine: A Breakthrough in the Treatment of Peptic Ulcer Disease

Discovery of Potent Nonpeptide Vasopressin Receptor Antagonists

• Genesis of the Vasopressin Receptor Antagonist Project
• Vasopressin, Its Receptors, and Disease
• The Game Plan
• Novel Chemotypes: Variations on a Theme
• Azepinoindoles
• Bridged Bicyclic Derivatives
• Thiazino-, Oxazino-, and Pyrazinobenzodiazepines

Discovery and Development of the Ultrashort-Acting Analgesic Remifentanil

• Discovery of Remifentanil
• Chemical Development of Remifentanil
• Human Clinical Trials with Remifentanil

Discovery and Development of Nevirapine

• Lead Discovery and Optimization
• Chemical Development and Process Research
• Mechanism of Action

Applications of Nuclear Imaging in Drug Discovery and Development

• Process and Challenges of Drug Development
• Role and Contribution of Position Emission Tomography
• Principles and Evolution of Technology
• Introduction to PET Principles
• Suitable Targets
• Suitable Animal Models
• Role in Drug Discovery
• Target Validation and Drug Design
• Preclinical Studies

Polymeric Sequestrants as Nonabsorbed Human Therapeutics

• Polymers as Specifi c Molecular Sequestrants
• Sequestration of Inorganic Ions in the GI Tract
• Polymeric Potassium Sequestrants: A Nonabsorbed Therapy for Hyperkalemia
• Polymeric Drugs for Chronic Renal Failure
• Polymeric Iron Sequestrants for the Treatment of Iron Overload Disorders
• Sequestration of Bile Acids: Polymers as Cholesterol-Lowering Agents
• Sequestration of Pathogens: Polymeric Anti-infective Agents
• Sequestration of Toxins
• Polymeric Antimicrobial Agents

Botanical Immunomodulators and Chemoprotectants in Cancer Therapy

• Immunomodulation
• Ethnopharmacology and Botanical Immunomodulators
• Adaptogens or Adjustive Medicine
• Botanicals with Adaptogenic Activity
• Rasayana Botanicals as Adaptogens
• Chemoprotection
• Drug Targets and Current Trends
• Chemoprotectants for Antimetabolites
• Thiol-Based Chemoprotectants for Cisplatin and Oxazophosphorine-Based Alkylating Agents
• Chemoprotectants for Anthracyclines
• Botanical Immunomodulators as Chemoprotectants
• Radioprotection
• Radioprotectants from Botanicals
• Botanical Immunomodulators as Antitumor Agents

Index

Also available:
Drug Discovery and Development Volume 1: Drug Discovery
Drug Discovery and Development 2-Volume Set

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