Analogue-based Drug Discovery III


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 ...

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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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Editorial Reviews

From the Publisher
“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)
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Product Details

  • ISBN-13: 9783527330737
  • Publisher: Wiley
  • Publication date: 2/18/2013
  • Edition number: 1
  • Pages: 404
  • Product dimensions: 6.80 (w) x 9.70 (h) x 0.90 (d)

Meet 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.

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Table of 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 Optimization of Beta-Adrenergic Receptor Blockers 10

1.2.2 Dual-Acting Drugs from Monotarget Drugs 11 Dual-Acting Opioid Drugs 11

1.3 Multitarget Drugs 12

1.3.1 Multitarget Drug Analogue to Eliminate a Side Effect 12 Clozapine and Olanzapine 12

1.3.2 Selective Drug Analogue from a Pioneer Multitarget Drug 13 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: (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-yl acetate 147

6.3 Direct-Acting P2Y12 Antagonists 152

6.3.1 Nucleoside-Containing Antagonists 152 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 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 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. 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 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 Phase I and II Studies 332 Clinical Pharmacokinetics 333 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

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