Successful Drug Discovery Vol.2 (Successful Drug Discovery Vol.2) （1. Auflage. 2016. 292 S. 120 SW-Abb., 40 Farbabb. 244 mm）

Herausgegeben von Fischer, Janos/ Childers, Wayne E.

WILEY-VCH（2016発売）

WILEY-VCH（2016発売）

• 製本 Hardcover:ハードカバー版
• 商品コード 9783527341153

Full 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.

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
.5 Conclusion 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-Binding Thiol Family of Natural Product HDAC Inhibitors 18
2.4 Synthetic Analogues of the Zinc-BindingThiol Natural Products 21
2.5 Summary 23

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
3.3 Belinostat Biological Profiling 41
3.4 Formulation Development 44
3.5 Clinical Development 45
3.6 Conclusions 52

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

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
5.2 Discovery of Chidamide 93
5.3 Molecular Mechanisms of Chidamide 97
5.4 Animal Studies 101
5.5 Clinical Development 101
5.6 Future Perspective 106

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
6.4 Physical Characterisation 129
6.5 Clinical Studies 129
6.6 Conclusion 132

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
7.5 Preclinical Data of Delamanid 151
7.6 Clinical Data of Delamanid 155
7.7 Future Priorities and Conclusion 158

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
8.3 Conclusion 183

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 the Treatment ofMDD 200
9.4 Uncovering Vortioxetine's Potential toTreat Cognitive Dysfunction in Patients with MDD 201

9.5 Conclusion 208

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

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
11.5 Nonclinical Drug Metabolism and Pharmacokinetics 250
11.6 Clinical Pharmacokinetics 251
11.7 Toxicology 252
11.8 Phase III Clinical Data 253
11.9 Other Oncology Studies 256
11.10 Conclusions 257

References 258
Index 267