Main 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 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 Sanchez 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