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Analogue-based Drug Discovery III

Analogue-based Drug Discovery III

János Fischer (Editor), C. Robin Ganellin (Editor), David P. Rotella (Editor)

ISBN: 978-3-527-65108-5

Dec 2012

404 pages

Description

Most drugs are analogue drugs. There are no general rules how a new drug can be discovered, nevertheless, there are some observations which help to find a new drug, and also an individual story of a drug discovery can initiate and help new discoveries. Volume III is a continuation of the successful book series with new examples of established and recently introduced drugs.
The major part of the book is written by key inventors either as a case study or a study of an analogue class. With its wide range across a variety of therapeutic fields and chemical classes, this is of interest to virtually every researcher in drug discovery and pharmaceutical chemistry, and -- together with the previous volumes -- constitutes the first systematic approach to drug analogue development.
PREFACE

PART I: General Aspects

PIONEER AND ANALOGUE DRUGS
Monotarget Drugs
Dual-Acting Drugs
Multitarget Drugs
Summary

COMPETITION IN THE PHARMACEUTICAL DRUG DEVELOPMENT
Introduction
Analogue-Based Drugs: Just Copies?
How Often Does Analogue-Based Activity Occur? Insights from the GPCR Patent Space

METABOLIC STABILITY AND ANALOGUE-BASED DRUG DISCOVERY
Introduction
Metabolism-Guided Drug Design
Indirect Modulation of Metabolism by Fluorine Substitution
Modulation of Low Clearance/Long Half-Life via Metabolism-Guided Design
Tactics to Resolve Metabolism Liabilities Due to Non-CYP Enzymes
Eliminating RM Liabilities in Drug Design
Eliminating Metabolism-Dependent Mutagenicity
Eliminating Mechanism-Based Inactivation of CYP Enzymes
Identification (and Elimination) of Electrophilic Lead Chemical Matter
Mitigating Risks of Idiosyncratic Toxicity via Elimination of RM Formation
Case Studies on Elimination of RM Liability in Drug Discovery
Concluding Remarks

USE OF MACROCYCLES IN DRUG DESIGN EXEMPLIFIED WITH ULIMORELIN, A POTENTIAL GHRELIN AGONIST FOR GASTROINTESTINAL MOTILITY DISORDERS
Introduction
High-Throughput Screening Results and Hit Selection
Macrocycle Structure -
Activity Relationships
PK -
ADME Considerations
Structural Studies
Preclinical Evaluation
Clinical Results and Current Status
Summary

PART II: Drug Classes

THE DISCOVERY OF ANTICANCER DRUGS TARGETING EPIGENETIC ENZYMES
Epigenetics
DNA Methyltransferases
5-Azacytidine (Azacitidine, Vidaza) and 5-Aza-20-deoxycytidine (Decitabine, Dacogen)
Other Nucleoside DNMT Inhibitors
Preclinical
Zinc-Dependent Histone Deacetylases
Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat, Zolinza)
FK228 (Depsipeptide, Romidepsin, Istodax)
Carboxylic Acid and Benzamide HDAC Inhibitors
Prospects for HDAC Inhibitors
Epigenetic Drugs - A Slow Start but a Bright Future

THIENOPYRIDYL AND DIRECT-ACTING P2Y12 RECEPTOR ANTAGONIST ANTIPLATELET DRUGS
Introduction
Thienopyridines
Direct-Acting P2Y12 Antagonists
cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin- 3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol
Summary

SELECTIVE ESTROGEN RECEPTOR MODULATORS
Introduction
Tamoxifen
Raloxifene
Summary

DISCOVERY OF NONPEPTIDE VASOPRESSIN V2 RECEPTOR ANTAGONISTS
Introduction
Peptide AVP Agonists and Antagonists
Lead Generation Strategies
Lead Generation Strategy-2, V2 Receptor Affinity
Lead Optimization
Reported Nonpeptide Vasopressin V2 Receptor Antagonist Compounds
Conclusions

THE DEVELOPMENT OF CYSTEINYL LEUKOTRIENE RECEPTOR ANTAGONISTS
Introduction
Scope of the Drug Discovery Effort on Leukotriene Modulators
Synthetic Leukotriene Production and Benefits Derived from this Effort
Bioassays and General Drug Discovery Testing Cascade
Development of Antagonists - General Approaches
Discovery of Zafirlukast
Discovery of Montelukast
Discovery of Pranlukast
Comparative Analysis and Crossover Impact
Postmarketing Issues
Conclusions

PART III: Case Studies

THE DISCOVERY OF DABIGATRAN ETEXILATE
Introduction
Dabigatran Design Story
Preclinical Pharmacology Molecular Mechanism of Action of Dabigatran
Clinical Studies and Indications
Summary

THE DISCOVERY OF CITALOPRAM AND ITS REFINEMENT TO ESCITALOPRAM
Introduction
Discovery of Talopram
Discovery of Citalopram
Synthesis and Production of Citalopram
The Pharmacological Profile of Citalopram
Clinical Efficacy of Citalopram
Synthesis and Production of Escitalopram
The Pharmacological Profile of the Citalopram Enantiomers
R-Citalopram's Surprising Inhibition of Escitalopram
Binding Site(s) for Escitalopram on the Serotonin Transporter
Future Perspectives on the Molecular Basis for Escitalopram?s Interaction with the SERT
Clinical Efficacy of Escitalopram
Conclusions

TAPENTADOL - FROM MORPHINE AND TRAMADOL TO THE DISCOVERY OF TAPENTADOL
Introduction
The Discovery of Tapentadol
The Preclinical and Clinical Profile of Tapentadol
Summary

NOVEL TAXANES: CABAZITAXEL CASE STUDY
Introduction
Cabazitaxel Structure -
Activity Relationships and Chemical Synthesis
Cabazitaxel Preclinical and Clinical Development
Summary

DISCOVERY OF BOCEPREVIR AND NARLAPREVIR: A CASE STUDY FOR ROLE OF STRUCTURE-BASED DRUG DESIGN

A NEW-GENERATION URIC ACID PRODUCTION INHIBITOR: FEBUXOSTAT
Introduction
Xanthine Oxidoreductase - Target Protein for Gout Treatment
Mechanism of XOR Inhibition by Allopurinol
Development of Nonpurine Analogue Inhibitor of XOR: Febuxostat
Mechanism of XOR Inhibition by Febuxostat
Excretion of XOR Inhibitors
Results of Clinical Trials of Febuxostat in Patients with Hyperuricemia and Gout
Summary
Added in proof

INDEX

“The book’s 15 chapters and 40 authors from 9 countries bring important, successful drug discoveries closer to medicinal chemists and all who are interested in the history of drug discoveries.  The major part of the chapters are written by key inventors.”  (Chemistry International, 1 January 2013)