Analogue-based Drug Discovery. Vol.3

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.

List of contents

PREFACEPART I: General AspectsPIONEER AND ANALOGUE DRUGSMonotarget DrugsDual-Acting Drugs Multitarget Drugs Summary COMPETITION IN THE PHARMACEUTICAL DRUG DEVELOPMENTIntroduction Analogue-Based Drugs: Just Copies? How Often Does Analogue-Based Activity Occur? Insights from the GPCR Patent Space METABOLIC STABILITY AND ANALOGUE-BASED DRUG DISCOVERYIntroduction 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 MatterMitigating 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 RelationshipsPK - ADME ConsiderationsStructural 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 PreclinicalZinc-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 DRUGSIntroduction 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 SummarySELECTIVE ESTROGEN RECEPTOR MODULATORS Introduction Tamoxifen Raloxifene Summary DISCOVERY OF NONPEPTIDE VASOPRESSIN V2 RECEPTOR ANTAGONISTS Introduction Peptide AVP Agonists and Antagonists Lead Generation StrategiesLead 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 ZafirlukastDiscovery of Montelukast Discovery of Pranlukast Comparative Analysis and Crossover Impact Postmarketing Issues ConclusionsPART III: Case Studies THE DISCOVERY OF DABIGATRAN ETEXILATEIntroduction Dabigatran Design Story Preclinical Pharmacology Molecular Mechanism of Action of DabigatranClinical Studies and IndicationsSummary THE DISCOVERY OF CITALOPRAM AND ITS REFINEMENT TO ESCITALOPRAM IntroductionDiscovery of Talopram Discovery of CitalopramSynthesis and Production of CitalopramThe 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 EscitalopramBinding Site(s) for Escitalopram on the Serotonin Transporter Future Perspectives on the Molecular Basis for Escitalopram?s Interaction with the SERT Clinical Efficacy of EscitalopramConclusionsTAPENTADOL - FROM MORPHINE AND TRAMADOL TO THE DISCOVERY OF TAPENTADOL IntroductionThe 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 DevelopmentSummary 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

About the author

János Fischer is a Senior Research Scientist at Richter Plc., Budapest, Hungary. He received his MSc and PhD degrees in organic chemistry from the Eotvos University of Budapest under Professor A. Kucsman. Between 1976 and 1978, he was a Humboldt Fellow at the University of Bonn under Professor W. Steglich. He has worked at Richter Plc. since 1981 where he participated in the research and development of leading cardiovascular drugs in Hungary. His main interest is analogue based drug discovery. He is the author of some 100 patents and scientific publications. In 2004, he was elected as a Titular member of the Chemistry and Human Health Division of IUPAC. He received an honorary professorship at the Technical University of Budapest.

C. Robin Ganellin studied Chemistry at London University, receiving a PhD in 1958 under Professor Michael Dewar, and was a Research Associate at MIT with Arthur Cope in 1960. He then joined Smith Kline & French Laboratories in the UK and was one of the co inventors of the revolutionary drug, cimetidine (also known as Tagamet). In 1986, he was made a Fellow of the Royal Society and appointed to the SK&F Chair of Medicinal Chemistry at University College London, where he is now Professor Emeritus of Medicinal Chemistry. Professor Ganellin is co inventor of over 160 patents and has authored over 260 scientific publications. He was President of the Medicinal Chemistry Section of the IUPAC and is Chairman of the IUPAC Subcommittee on Medicinal Chemistry and Drug Development.

David Rotella is the Margaret and Herman Sokol Professor of Medicinal Chemistry at Montclair State University. He earned a B.S. Pharm. degree at the University of Pittsburgh (1981) and a Ph.D. (1985) at The Ohio State University with Donald. T. Witiak. After postdoctoral studies in organic chemistry at Penn State University with Ken S. Feldman, he was an assistant professor at the University of Mississippi. David worked at Cephalon, Bristol-Myers, Lexicon and Wyeth where he was involved in neurodegeneration, schizophrenia, cardiovascular and metabolic disease drug discovery projects.

Summary

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.

Report

"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)

Product details

• Authors: Janos Fischer, János Fischer, C. Robin Ganellin, David P. Rotella
• Assisted by: Janos Fischer (Editor), János Fischer (Editor), C. Robin Ganellin (Editor), David P Rotella (Editor), Robin Ganellin (Editor), C Robin Ganellin (Editor), David P. Rotella (Editor)
• Publisher: Wiley-VCH
• Languages: English
• Product format: Hardback
• Released: 01.12.2012
• EAN: 9783527330737
• ISBN: 978-3-527-33073-7
• No. of pages: 386
• Dimensions: 177 mm x 249 mm x 25 mm
• Weight: 1016 g
• Illustrations: 125 SW-Abb., 20 Farbabb., 33 Tabellen
• Subjects: Natural sciences, medicine, IT, technology > Chemistry; Chemie, Arzneimittel, wirkstoff, chemistry, Natural Products, Naturstoffchemie, Wirkstoffforschung u. -entwicklung, Drug Discovery & Development, Molecular Pharmacology, Molekulare Pharmakologie, PHARMAZEUTISCHE CHEMIE, Analogwirkstoff