Analogue-Based Drug Discovery III

Analogue-Based Drug Discovery III

By: Janos Fischer (editor), David P. Rotella (editor), Professor C. Robin Ganellin (editor)Hardback

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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.

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About Author

Janos 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.

Contents

Preface XIII List of Contributors XV Part I General Aspects 1 1 Pioneer and Analogue Drugs 3 Janos Fischer, C. Robin Ganellin, and David P. Rotella 1.1 Monotarget Drugs 5 1.1.1 H2 Receptor Histamine Antagonists 5 1.1.2 ACE Inhibitors 6 1.1.3 DPP IV Inhibitors 7 1.1.4 Univalent Direct Thrombin Inhibitors 8 1.2 Dual-Acting Drugs 10 1.2.1 Monotarget Drugs from Dual-Acting Drugs 10 1.2.1.1 Optimization of Beta-Adrenergic Receptor Blockers 10 1.2.2 Dual-Acting Drugs from Monotarget Drugs 11 1.2.2.1 Dual-Acting Opioid Drugs 11 1.3 Multitarget Drugs 12 1.3.1 Multitarget Drug Analogue to Eliminate a Side Effect 12 1.3.1.1 Clozapine and Olanzapine 12 1.3.2 Selective Drug Analogue from a Pioneer Multitarget Drug 13 1.3.2.1 Selective Serotonin Reuptake Inhibitors 13 1.4 Summary 16 Acknowledgments 16 References 16 2 Competition in the Pharmaceutical Drug Development 21 Christian Tyrchan and Fabrizio Giordanetto 2.1 Introduction 21 2.2 Analogue-Based Drugs: Just Copies? 22 2.3 How Often Does Analogue-Based Activity Occur? Insights from the GPCR Patent Space 25 References 32 3 Metabolic Stability and Analogue-Based Drug Discovery 37 Amit S. Kalgutkar and Antonia F. Stepan List of Abbreviations 37 3.1 Introduction 37 3.2 Metabolism-Guided Drug Design 39 3.3 Indirect Modulation of Metabolism by Fluorine Substitution 42 3.4 Modulation of Low Clearance/Long Half-Life via Metabolism-Guided Design 45 3.5 Tactics to Resolve Metabolism Liabilities Due to Non-CYP Enzymes 46 3.5.1 Aldehyde Oxidase 46 3.5.2 Monoamine Oxidases 48 3.5.3 Phase II Conjugating Enzymes (UGTand Sulfotransferases) 49 3.6 Eliminating RM Liabilities in Drug Design 51 3.7 Eliminating Metabolism-Dependent Mutagenicity 51 3.8 Eliminating Mechanism-Based Inactivation of CYP Enzymes 54 3.9 Identification (and Elimination) of Electrophilic Lead Chemical Matter 60 3.10 Mitigating Risks of Idiosyncratic Toxicity via Elimination of RM Formation 61 3.11 Case Studies on Elimination of RM Liability in Drug Discovery 62 3.12 Concluding Remarks 67 References 68 4 Use of Macrocycles in Drug Design Exemplified with Ulimorelin, a Potential Ghrelin Agonist for Gastrointestinal Motility Disorders 77 Mark L. Peterson, Hamid Hoveyda, Graeme Fraser, Eric Marsault, and Rene Gagnon 4.1 Introduction 77 4.1.1 Ghrelin as a Novel Pharmacological Target for GI Motility Disorders 77 4.1.2 Macrocycles in Drug Discovery 79 4.1.3 Tranzyme Technology 80 4.2 High-Throughput Screening Results and Hit Selection 82 4.3 Macrocycle Structure Activity Relationships 83 4.3.1 Preliminary SAR 83 4.3.2 Ring Size and Tether 83 4.3.3 Amino Acid Components 87 4.3.4 Further Tether Optimization 89 4.4 PK ADME Considerations 92 4.5 Structural Studies 95 4.6 Preclinical Evaluation 96 4.6.1 Additional Compound Profiling 97 4.6.2 Additional Pharmacokinetic Data 98 4.6.3 Animal Models for Preclinical Efficacy 100 4.7 Clinical Results and Current Status 100 4.8 Summary 103 References 104 Part II Drug Classes 111 5 The Discovery of Anticancer Drugs Targeting Epigenetic Enzymes 113 A. Ganesan List of Abbreviations 113 5.1 Epigenetics 114 5.2 DNA Methyltransferases 116 5.3 5-Azacytidine (Azacitidine, Vidaza) and 5-Aza-20-deoxycytidine (Decitabine, Dacogen) 118 5.4 Other Nucleoside DNMT Inhibitors 122 5.5 Preclinical DNMT Inhibitors 123 5.6 Zinc-Dependent Histone Deacetylases 124 5.7 Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat, Zolinza) 125 5.8 FK228 (Depsipeptide, Romidepsin, Istodax) 127 5.9 Carboxylic Acid and Benzamide HDAC Inhibitors 131 5.10 Prospects for HDAC Inhibitors 132 5.11 Epigenetic Drugs A Slow Start but a Bright Future 133 Acknowledgments 133 References 134 6 Thienopyridyl and Direct-Acting P2Y12 Receptor Antagonist Antiplatelet Drugs 141 Joseph A. Jakubowski and Atsuhiro Sugidachi List of Abbreviations 141 6.1 Introduction 142 6.1.1 Platelet Involvement in Atherothrombosis 142 6.2 Thienopyridines 143 6.2.1 Ticlopidine: 5-[(2-Chlorophenyl)methyl)-4,5,6,7-tetrahydrothieno[3,2-c] pyridine 144 6.2.2 Clopidogrel: (p)-(S)-a-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-c] pyridine-5(4H) acetate 145 6.2.3 Prasugrel: 5-[(1RS)-2-Cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl acetate 147 6.3 Direct-Acting P2Y12 Antagonists 152 6.3.1 Nucleoside-Containing Antagonists 152 6.3.1.1 Cangrelor: [Dichloro-[[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl)purin-9-yl] oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]methyl] phosphonic acid 153 6.3.1.2 Ticagrelor: (1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl) cyclopropylamino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin- 3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol 154 6.3.2 Non-Nucleoside P2Y12 Antagonists 157 6.3.2.1 Elinogrel: N-[(5-Chlorothiophen-2-yl)sulfonyl]-N0-{4-[6-fluoro-7-(methylamino)-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl]phenyl} urea 157 6.4 Summary 158 References 158 7 Selective Estrogen Receptor Modulators 165 Amarjit Luniwal, Rachael Jetson, and Paul Erhardt List of Abbreviations 165 7.1 Introduction 166 7.1.1 Working Definition 166 7.1.2 Early ABDD Leading to a Pioneer SERM 167 7.1.3 Discovery and Development of Clomiphene 169 7.1.4 SERM-Directed ABDD: General Considerations 170 7.2 Tamoxifen 171 7.2.1 Early Development 171 7.2.2 Clinical Indications and Molecular Action 172 7.2.3 Pharmacokinetics and Major Metabolic Pathways 174 7.2.4 Clinical Toxicity and New Tamoxifen Analogues 175 7.3 Raloxifene 175 7.3.1 Need for New Antiestrogens 176 7.3.2 Design and Initial Biological Data on Raloxifene 176 7.3.3 RUTH Study 177 7.3.4 STAR Study 177 7.3.5 Binding to the Estrogen Receptor 178 7.3.6 ADME 179 7.3.7 Further Research 179 7.4 Summary 179 References 180 8 Discovery of Nonpeptide Vasopressin V2 Receptor Antagonists 187 Kazumi Kondo and Hidenori Ogawa List of Abbreviations 187 8.1 Introduction 187 8.2 Peptide AVP Agonists and Antagonists 188 8.3 Lead Generation Strategies 189 8.4 Lead Generation Strategy-2, V2 Receptor Affinity 192 8.5 Lead Optimization 197 8.6 Reported Nonpeptide Vasopressin V2 Receptor Antagonist Compounds 199 8.6.1 Sanofi 199 8.6.2 Astellas (Yamanouchi) 199 8.6.3 Wyeth 201 8.6.4 Johnson & Johnson 201 8.6.5 Wakamoto Pharmaceutical Co. Ltd 202 8.6.6 Japan Tobacco Inc. 202 8.7 Conclusions 203 References 203 9 The Development of Cysteinyl Leukotriene Receptor Antagonists 211 Peter R. Bernstein List of Abbreviations 211 9.1 Introduction 212 9.2 Scope of the Drug Discovery Effort on Leukotriene Modulators 214 9.3 Synthetic Leukotriene Production and Benefits Derived from this Effort 215 9.4 Bioassays and General Drug Discovery Testing Cascade 216 9.5 Development of Antagonists General Approaches 218 9.6 Discovery of Zafirlukast 218 9.7 Discovery of Montelukast 224 9.8 Discovery of Pranlukast 227 9.9 Comparative Analysis and Crossover Impact 229 9.10 Postmarketing Issues 231 9.11 Conclusions 232 Acknowledgment 232 Disclaimer 232 References 233 Part III Case Studies 241 10 The Discovery of Dabigatran Etexilate 243 Norbert Hauel, Andreas Clemens, Herbert Nar, Henning Priepke, Joanne van Ryn, and Wolfgang Wienen List of Abbreviations 243 10.1 Introduction 243 10.2 Dabigatran Design Story 246 10.3 Preclinical Pharmacology Molecular Mechanism of Action of Dabigatran 254 10.3.1 In Vitro Antihemostatic Effects of Dabigatran 255 10.3.2 Ex Vivo Antihemostatic Effects of Dabigatran/Dabigatran Etexilate 256 10.3.3 Venous and Arterial Antithrombotic Effects of Dabigatran/Dabigatran Etexilate 256 10.3.4 Mechanical Heart Valves 257 10.3.5 Cancer 257 10.3.6 Fibrosis 257 10.3.7 Atherosclerosis 258 10.4 Clinical Studies and Indications 258 10.4.1 Prevention of Deep Venous Thrombosis 259 10.4.2 Therapy of Venous Thromboembolism 259 10.4.3 Stroke Prevention in Patients with Atrial Fibrillation 260 10.4.4 Prevention of Recurrent Myocardial Infarction in Patients with Acute Coronary Syndrome 260 10.5 Summary 260 References 261 11 The Discovery of Citalopram and Its Refinement to Escitalopram 269 Klaus P. Bogeso and Connie Sanchez List of Abbreviations 269 11.1 Introduction 270 11.2 Discovery of Talopram 271 11.3 Discovery of Citalopram 272 11.4 Synthesis and Production of Citalopram 275 11.5 The Pharmacological Profile of Citalopram 276 11.6 Clinical Efficacy of Citalopram 277 11.7 Synthesis and Production of Escitalopram 278 11.8 The Pharmacological Profile of the Citalopram Enantiomers 279 11.9 R-Citalopram s Surprising Inhibition of Escitalopram 279 11.10 Binding Site(s) for Escitalopram on the Serotonin Transporter 283 11.11 Future Perspectives on the Molecular Basis for Escitalopram s Interaction with the SERT 286 11.12 Clinical Efficacy of Escitalopram 287 11.13 Conclusions 288 References 288 12 Tapentadol From Morphine and Tramadol to the Discovery of Tapentadol 295 Helmut Buschmann List of Abbreviations 295 12.1 Introduction 296 12.1.1 Pain and Current Pain Treatment Options 297 12.1.2 Pain Research Today 300 12.1.3 The Complex Mode of Action of Tramadol 301 12.2 The Discovery of Tapentadol 302 12.2.1 From the Tramadol Structure to Tapentadol 303 12.2.2 Synthetic Pathways to Tapentadol 306 12.3 The Preclinical and Clinical Profile of Tapentadol 310 12.3.1 Preclinical Pharmacology of Tapentadol 311 12.3.2 Clinical Trials 312 12.3.3 Pharmacokinetics and Drug Drug Interactions of Tapentadol 314 12.4 Summary 315 References 315 13 Novel Taxanes: Cabazitaxel Case Study 319 Herve Bouchard, Dorothee Semiond, Marie-Laure Risse, and Patricia Vrignaud List of Abbreviations 319 13.1 Introduction 320 13.1.1 Isolation and Chemical Synthesis of Taxanes 321 13.1.2 Drug Resistance and Novel Taxanes 322 13.2 Cabazitaxel Structure Activity Relationships and Chemical Synthesis 323 13.2.1 Chemical and Physical Properties 323 13.2.2 Structure Activity Relationships of Cabazitaxel 324 13.2.3 Chemical Synthesis of Cabazitaxel 325 13.3 Cabazitaxel Preclinical and Clinical Development 328 13.3.1 Preclinical Development 328 13.3.2 Clinical Studies 330 13.3.2.1 Phase I and II Studies 332 13.3.2.2 Clinical Pharmacokinetics 333 13.3.2.3 Phase III Trial 334 13.3.3 Other Ongoing Trials 335 13.4 Summary 336 Acknowledgments 337 References 337 14 Discovery of Boceprevir and Narlaprevir: A Case Study for Role of Structure-Based Drug Design 343 Srikanth Venkatraman, Andrew Prongay, and George F. Njoroge List of Abbreviations 343 References 359 15 A New-Generation Uric Acid Production Inhibitor: Febuxostat 365 Ken Okamoto, Shiro Kondo, and Takeshi Nishino List of Abbreviations 365 15.1 Introduction 365 15.2 Xanthine Oxidoreductase Target Protein for Gout Treatment 367 15.3 Mechanism of XOR Inhibition by Allopurinol 368 15.4 Development of Nonpurine Analogue Inhibitor of XOR: Febuxostat 369 15.5 Mechanism of XOR Inhibition by Febuxostat 370 15.6 Excretion of XOR Inhibitors 372 15.7 Results of Clinical Trials of Febuxostat in Patients with Hyperuricemia and Gout 372 15.8 Summary 373 15.9 Added in proof 373 References 373 Index 377

Product Details

  • publication date: 19/12/2012
  • ISBN13: 9783527330737
  • Format: Hardback
  • Number Of Pages: 404
  • ID: 9783527330737
  • weight: 1018
  • ISBN10: 3527330739

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