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Successful Drug Discovery, Volume 2

Janos Fischer (Editor), Wayne E. Childers (Editor)
ISBN: 978-3-527-34115-3
292 pages
June 2017
Successful Drug Discovery, Volume 2 (3527341153) cover image

Description

Retaining the successful approach found in the previous volume in this series, the inventors and primary developers of drugs that successfully made it to market tell the story of the drug's discovery and development and relate the often twisted route from the first candidate molecule to the final marketed drug.
11 selected case studies describe recently introduced drugs that have not been previously covered in textbooks or general references. These range across six different therapeutic fields and provide a representative cross-section of the current drug development efforts. Backed by copious data and chemical information, the insight and experience of the contributors makes this one of the most useful training manuals that a junior medicinal chemist can hope to find and has won the support and endorsement of IUPAC.
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Table of Contents

Preface XIII

List of Contributors XVII

Part I HDAC Inhibitor Anticancer Drug Discovery 1

1 From DMSO to the Anticancer Compound SAHA, an Unusual Intellectual Pathway for Drug Design 3
Ronald Breslow

1.1 Introduction 3

1.2 The Discovery of SAHA (vorinostat) 4

1.3 Clinical Trials 7

1.4 Follow-On Research – Selective HDAC Inhibitors 8

1.5 Conclusion 9

References 9

2 Romidepsin and the Zinc-Binding Thiol Family of Natural Product HDAC Inhibitors 13
A. Ganesan

2.1 Histone Deacetylases as a Therapeutic Target 13

2.2 The Discovery and Development of Romidepsin 15

2.3 The Zinc-BindingThiol Family of Natural Product HDAC Inhibitors 18

2.4 Synthetic Analogues of the Zinc-BindingThiol Natural Products 21

2.5 Summary 23

References 24

3 The Discovery and Development of Belinostat 31
Paul W. Finn, Einars Loza and Elisabeth Carstensen

3.1 Introduction 31

3.2 Discovery of Belinostat 32

3.2.1 Design Strategy 32

3.2.2 Medicinal Chemistry and SAR 34

3.3 Belinostat Biological Profiling 41

3.3.1 Mode of Action and HDAC Isoform Selectivity 41

3.3.2 Antiproliferative and Antitumor Activity 42

3.4 Formulation Development 44

3.5 Clinical Development 45

3.5.1 Clinical Studies Leading to Approval and Other Clinical Investigations 45

3.5.2 Pharmacokinetics 49

3.5.3 Safety and Tolerability 51

3.6 Conclusions 52

References 53

4 Discovery and Development of Farydak (NVP-LBH589,Panobinostat) as an Anticancer Drug 59
Peter Atadja and Lawrence Perez

4.1 Target Identification: From p21Waf1 Induction to HDAC Inhibition 59

4.2 Program Flowchart Assays for Drug Discovery 61

4.3 Hit-To-Lead Campaign: Trichostatin A to LAK974 63

4.4 Lead Optimization: LAK974 to LAQ824 64

4.5 Profiling LAQ824 for Cancer Therapy 66

4.6 Preclinical Development of LAQ824 70

4.7 LAQ824 Follow-Up 72

4.8 Discovery of LBH589 73

4.9 Safety Profile for LBH589 74

4.10 Pan-HDAC Inhibition by LBH589 76

4.11 Cancer Cell-Specific Cytotoxicity of LBH589 76

4.11.1 Toxicity and Safety Studies with LBH589 78

4.11.2 Early Clinical Activity of LBH589 in CTCL 78

4.11.3 Large-Scale Cell Line Profiling to Discover Lineage-Specific LBH589-Sensitive Cancer Indications 79

4.11.4 Clinical Profiling ofHemeMalignancies for LBH589Activity 80

4.11.5 Phase II Study of Oral Panobinostat in Hodgkin Lymphoma 81

4.11.6 Phase IB Clinical Studies in MultipleMyeloma 82

4.11.7 Phase III Registration Study inRelapsed orRefractoryMyeloma 82

4.11.8 Conclusion and Future Perspective 83

References 85

5 Discovery and Development of HDAC Subtype Selective Inhibitor Chidamide: Potential Immunomodulatory Activity Against Cancers 89
Xian-Ping Lu, Zhi-Qiang Ning, Zhi-Bin Li, De-Si Pan, Song Shan, Xia Guo, Hai-Xiang Cao, Jin-Di Yu and Qian-Jiao Yang

5.1 Introduction 89

5.1.1 Epigenetics and Cancer 89

5.1.2 Epigenetic Drugs 90

5.2 Discovery of Chidamide 93

5.2.1 Identification of Chemical Scaffold 93

5.2.2 Design and ScreeningNewSelective BenzamideHDACInhibitors 93

5.2.3 Molecular Docking of Chidamide with HDAC2 95

5.3 Molecular Mechanisms of Chidamide 97

5.3.1 Selectivity 97

5.3.2 Induction of Cell Cycle Arrest, Apoptosis and Differentiation of Tumour Cells 98

5.3.3 Reversal of Epithelial toMesenchymal Transition 99

5.3.4 Stimulation of Innate andAntigen-SpecificAntitumour Immunity 99

5.3.5 Multiplicity of Anticancer Mechanisms by Chidamide 100

5.4 Animal Studies 101

5.5 Clinical Development 101

5.5.1 Pharmacokinetics and Pharmacodynamics 101

5.5.2 Unmet Medical Needs for PeripheralT-Cell Lymphoma (PTCL) 102

5.5.3 Efficacy Assessment of Chidamide in PTCL Patients 103

5.5.4 Safety Profile 105

5.6 Future Perspective 106

References 108

Part II Steroidal CYP17 Inhibitor Anticancer Drug Discovery 115

6 Abiraterone Acetate (Zytiga): AnInhibitor of CYP17 as a Therapeutic for Castration-Resistant Prostate Cancer 117
Gabriel M. Belfort, Boyd L. Harrisonand Gabriel Martinez Botella

6.1 Introduction 117

6.2 Discovery and Structure–Activity Relationships (SAR) 119

6.3 Preclinical Characterisation of Abiraterone and Abiraterone Acetate 126

6.3.1 Pharmacology 126

6.3.2 Pharmacokinetics 127

6.3.3 Toxicology 128

6.4 Physical Characterisation 129

6.5 Clinical Studies 129

6.6 Conclusion 132

References 133

Part III Anti-Infective Drug Discoveries 137

7 Discovery of Delamanid for the Treatment of Multidrug-Resistant Pulmonary Tuberculosis 139
Hidetsugu Tsubouchi, Hirofumi Sasaki, Hiroshi Ishikawa and Makoto Matsumoto

7.1 Introduction 139

7.2 Synthesis Strategy 140

7.3 Synthesis Route 142

7.4 Screening Evaluations 145

7.4.1 Screening Procedure 145

7.4.2 Screening Results 146

7.4.3 Selection of a Compound Candidate for Preclinical Tests 151

7.5 Preclinical Data of Delamanid 151

7.5.1 Antituberculosis Activity 151

7.5.2 Mechanism of Action 153

7.5.3 Pharmacokinetics 153

7.5.4 Genotoxicity and Carcinogenicity 154

7.5.5 Preclinical Therapeutic Efficacy 154

7.6 Clinical Data of Delamanid 155

7.6.1 Clinical Pharmacokinetics 155

7.6.2 Drug–Drug Interactions 156

7.6.3 Cardiovascular Safety 156

7.6.4 Clinical Therapeutic Efficacy 156

7.6.5 Other Clinical Trials 157

7.7 Future Priorities and Conclusion 158

References 159

8 Sofosbuvir: The Discovery of a Curative Therapy for the Treatment of Hepatitis C Virus 163
Michael J. Sofia

8.1 Introduction 163

8.2 Discussion 165

8.2.1 Target Rationale: HCVNS5BRNA-Dependent RNA Polymerase 165

8.2.2 Rationale andDesign of a Liver Targeted Nucleotide Prodrug 168

8.2.3 Prodrug Optimization and Preclinical Evaluation 171

8.2.4 Prodrug Metabolism 175

8.2.5 Clinical Proof of Concept of a Liver Targeted Nucleotide Prodrug 176

8.2.6 The Single Diastereomer: Sofosbuvir 176

8.2.7 Sofosbuvir Preclinical Profile 177

8.2.8 Sofosbuvir Clinical Studies 179

8.2.9 Viral Resistance 182

8.3 Conclusion 183

References 184

Part IV Central Nervous System (CNS) Drug Discovery 189

9 The Discovery of the Antidepressant Vortioxetine and the Research that Uncovered Its Potential to Treat the Cognitive Dysfunction Associated with Depression 191
Benny Bang-Andersen, Christina Kurre Olsen and Connie Sanchéz

9.1 Introduction 191

9.2 The Discovery of Vortioxetine 192

9.3 Clinical Development of Vortioxetine for theTreatment ofMDD 200

9.4 UncoveringVortioxetine’s Potential toTreat Cognitive Dysfunction in Patients with MDD 201

9.4.1 Early Preclinical Evidence that Differentiated Vortioxetine from Other Antidepressants 201

9.4.2 Vortioxetine’s Primary Targets and Their Putative Impact on Cognitive Function – Early Preclinical Data 202

9.4.3 Hypothesis-Generating Clinical Study of Vortioxetine’s Effects on Cognitive Symptoms in Elderly Patients with MDD 203

9.4.4 Substantiation of a Mechanistic Rationale for the Procognitive Effects of Vortioxetine in Preclinical Models and Its Differentiation from SSRIs and SNRIs 204

9.4.5 Confirmation of the Cognitive Benefits of Vortioxetine in Two Large Placebo-Controlled Studies in Adults with MDD 205

9.4.6 Additional Translational Evidence of the Effect of Vortioxetine on Brain Activity During Cognitive Performance 208

9.5 Conclusion 208

References 210

Part V Antiulcer Drug Discovery 215

10 Discovery of Vonoprazan Fumarate (TAK-438) as a Novel, Potent and Long-Lasting Potassium-Competitive Acid Blocker 217
Haruyuki Nishida

10.1 Introduction 217

10.2 Limitations of PPIs and the Possibility of P-CABs 218

10.3 Exploration of Seed Compounds 220

10.4 Lead Generation from HTS Hit Compound 1 220

10.5 Analysis of SAR and Structure–Toxicity Relationship for Lead Optimization 223

10.6 Selection of Vonoprazan Fumarate (TAK-438) as a Candidate Compound 224

10.7 Preclinical Study of TAK-438 226

10.8 Clinical Study of TAK-438 228

10.9 Discussion 229

10.10 Conclusion 230

References 232

Part VI Cross-Therapeutic Drug Discovery (Respiratory Diseases/Anticancer) 235

11 Discovery and Development of Nintedanib: A Novel Antiangiogenic and Antifibrotic Agent 237
Gerald J. Roth,  Rudolf Binder, Florian Colbatzky, Claudia Dallinger, Rozsa Schlenker-Herceg, Frank Hilberg, Lutz Wollin, John Park, Alexander Pautsch and Rolf Kaiser

11.1 Introduction 237

11.2 Structure–Activity Relationships of Oxindole Kinase Inhibitors and the Discovery of Nintedanib 238

11.3 Structural Research 244

11.4 Preclinical Pharmacodynamic Exploration 246

11.4.1 Kinase Inhibition Profile of Nintedanib 246

11.4.2 Oncology, Disease Pathogenesis and Mechanism of Action 246

11.4.3 Idiopathic Pulmonary Fibrosis,Disease Pathogenesis andMechanism of Action 249

11.5 Nonclinical Drug Metabolism and Pharmacokinetics 250

11.6 Clinical Pharmacokinetics 251

11.7 Toxicology 252

11.8 Phase III Clinical Data 253

11.8.1 Efficacy and Safety of Nintedanib in IPF 253

11.8.2 Efficacy and Safety of Nintedanib in NSCLC 255

11.9 Other Oncology Studies 256

11.10 Conclusions 257

References 258

Index 267

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Author Information

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. Since 2014 he is Chair of the Subcommittee on Drug Discovery and Development of IUPAC. He received an honorary professorship at the Technical University of Budapest.

Wayne Childers is Associate Professor of Pharmaceutical Sciences at Temple University, Philadelphia, USA. Wayne received his BA (1979) degree from Vanderbilt University in chemistry and PhD (1984) in organic chemistry from the University of Georgia under the direction of Harold Pinnick. He served as an Assistant Adjunct Professor at Bucknell University before accepting a position as a postdoctoral fellow at the Johns Hopkins University School of Medicine in the laboratories of Dr. Cecil Robinson. He then joined Wyeth Research, Inc., working in numerous therapeutic areas, including psychiatric diseases, stroke, and Alzheimer's disease, and the treatment of chronic pain. He stayed with Wyeth for 22 years, before joining the faculty of Temple University in 2010.
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