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 Effect12 1.3.1.1 Clozapine and Olanzapine 12 1.3.2 Selective Drug Analogue from a Pioneer Multitarget Drug13 1.3.

2.1 Selective Serotonin Reuptake Inhibitors 13 1.4 Summary 16 Acknowledgments 16 References 16 2 Competition in the Pharmaceutical Drug Development21 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 fromthe GPCR Patent Space 25 References 32 3 Metabolic Stability and Analogue-Based Drug Discovery37 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 Substitution42 3.4 Modulation of Low Clearance/Long Half-Life viaMetabolism-Guided Design 45 3.5 Tactics to Resolve Metabolism Liabilities Due to Non-CYPEnzymes 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 Enzymes54 3.9 Identification (and Elimination) of Electrophilic LeadChemical Matter 60 3.10 Mitigating Risks of Idiosyncratic Toxicity via Eliminationof RM Formation 61 3.

11 Case Studies on Elimination of RM Liability in DrugDiscovery 62 3.12 Concluding Remarks 67 References 68 4 Use of Macrocycles in Drug Design Exemplified withUlimorelin, a Potential Ghrelin Agonist for GastrointestinalMotility 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 MotilityDisorders 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 EpigeneticEnzymes 113 A. Ganesan List of Abbreviations 113 5.

1 Epigenetics 114 5.2 DNA Methyltransferases 116 5.3 5-Azacytidine (Azacitidine, Vidaza) and5-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 Future133 Acknowledgments 133 References 134 6 Thienopyridyl and Direct-Acting P2Y12 Receptor AntagonistAntiplatelet 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] pyridine144 6.2.2 Clopidogrel:(þ)-(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-ylacetate 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 Antagonists187 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 AntagonistCompounds 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 ReceptorAntagonists 211 Peter R. Bernstein List of Abbreviations 211 9.1 Introduction 212 9.2 Scope of the Drug Discovery Effort on Leukotriene Modulators214 9.3 Synthetic Leukotriene Production and Benefits Derived fromthis Effort 215 9.

4 Bioassays and General Drug Discovery Testing Cascade 216 9.5 Development of Antagonists - General Approaches218 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 ofDabigatran 254 10.3.1 In Vitro Antihemostatic Effects of Dabigatran 255 10.3.2 Ex Vivo Antihemostatic Effects of Dabigatran/DabigatranEtexilate 256 10.3.

3 Venous and Arterial Antithrombotic Effects ofDabigatran/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 Fibrillation260 10.

4.4 Prevention of Recurrent Myocardial Infarction in Patientswith Acute Coronary Syndrome 260 10.5 Summary 260 References 261 11 The Discovery of Citalopram and Its Refinement toEscitalopram 269 Klaus P. Bøgesø 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 Enantiomers279 11.9 R-Citalopram''s Surprising Inhibition of Escitalopram279 11.10 Binding Site(s) for Escitalopram on the Sero.