Successful Drug Discovery, Volume 2

Janos 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.

• Preface XIIIList of Contributors XVIIPart I HDAC Inhibitor Anticancer Drug Discovery 11 From DMSO to the Anticancer Compound SAHA, an Unusual Intellectual Pathway for Drug Design 3Ronald Breslow1.1 Introduction 31.2 The Discovery of SAHA (vorinostat) 41.3 Clinical Trials 71.4 Follow-On Research – Selective HDAC Inhibitors 81.5 Conclusion 9References 92 Romidepsin and the Zinc-Binding Thiol Family of Natural Product HDAC Inhibitors 13A. Ganesan2.1 Histone Deacetylases as a Therapeutic Target 132.2 The Discovery and Development of Romidepsin 152.3 The Zinc-BindingThiol Family of Natural Product HDAC Inhibitors 182.4 Synthetic Analogues of the Zinc-BindingThiol Natural Products 212.5 Summary 23References 243 The Discovery and Development of Belinostat 31Paul W. Finn, Einars Loza and Elisabeth Carstensen3.1 Introduction 313.2 Discovery of Belinostat 323.2.1 Design Strategy 323.2.2 Medicinal Chemistry and SAR 343.3 Belinostat Biological Profiling 413.3.1 Mode of Action and HDAC Isoform Selectivity 413.3.2 Antiproliferative and Antitumor Activity 423.4 Formulation Development 443.5 Clinical Development 453.5.1 Clinical Studies Leading to Approval and Other Clinical Investigations 453.5.2 Pharmacokinetics 493.5.3 Safety and Tolerability 513.6 Conclusions 52References 534 Discovery and Development of Farydak (NVP-LBH589,Panobinostat) as an Anticancer Drug 59Peter Atadja and Lawrence Perez4.1 Target Identification: From p21Waf1 Induction to HDAC Inhibition 594.2 Program Flowchart Assays for Drug Discovery 614.3 Hit-To-Lead Campaign: Trichostatin A to LAK974 634.4 Lead Optimization: LAK974 to LAQ824 644.5 Profiling LAQ824 for Cancer Therapy 664.6 Preclinical Development of LAQ824 704.7 LAQ824 Follow-Up 724.8 Discovery of LBH589 734.9 Safety Profile for LBH589 744.10 Pan-HDAC Inhibition by LBH589 764.11 Cancer Cell-Specific Cytotoxicity of LBH589 764.11.1 Toxicity and Safety Studies with LBH589 784.11.2 Early Clinical Activity of LBH589 in CTCL 784.11.3 Large-Scale Cell Line Profiling to Discover Lineage-Specific LBH589-Sensitive Cancer Indications 794.11.4 Clinical Profiling ofHemeMalignancies for LBH589Activity 804.11.5 Phase II Study of Oral Panobinostat in Hodgkin Lymphoma 814.11.6 Phase IB Clinical Studies in MultipleMyeloma 824.11.7 Phase III Registration Study inRelapsed orRefractoryMyeloma 824.11.8 Conclusion and Future Perspective 83References 855 Discovery and Development of HDAC Subtype Selective Inhibitor Chidamide: Potential Immunomodulatory Activity Against Cancers 89Xian-Ping Lu, Zhi-Qiang Ning, Zhi-Bin Li, De-Si Pan, Song Shan, Xia Guo, Hai-Xiang Cao, Jin-Di Yu and Qian-Jiao Yang5.1 Introduction 895.1.1 Epigenetics and Cancer 895.1.2 Epigenetic Drugs 905.2 Discovery of Chidamide 935.2.1 Identification of Chemical Scaffold 935.2.2 Design and ScreeningNewSelective BenzamideHDACInhibitors 935.2.3 Molecular Docking of Chidamide with HDAC2 955.3 Molecular Mechanisms of Chidamide 975.3.1 Selectivity 975.3.2 Induction of Cell Cycle Arrest, Apoptosis and Differentiation of Tumour Cells 985.3.3 Reversal of Epithelial toMesenchymal Transition 995.3.4 Stimulation of Innate andAntigen-SpecificAntitumour Immunity 995.3.5 Multiplicity of Anticancer Mechanisms by Chidamide 1005.4 Animal Studies 1015.5 Clinical Development 1015.5.1 Pharmacokinetics and Pharmacodynamics 1015.5.2 Unmet Medical Needs for PeripheralT-Cell Lymphoma (PTCL) 1025.5.3 Efficacy Assessment of Chidamide in PTCL Patients 1035.5.4 Safety Profile 1055.6 Future Perspective 106References 108Part II Steroidal CYP17 Inhibitor Anticancer Drug Discovery 1156 Abiraterone Acetate (Zytiga): AnInhibitor of CYP17 as a Therapeutic for Castration-Resistant Prostate Cancer 117Gabriel M. Belfort, Boyd L. Harrisonand Gabriel Martinez Botella6.1 Introduction 1176.2 Discovery and Structure–Activity Relationships (SAR) 1196.3 Preclinical Characterisation of Abiraterone and Abiraterone Acetate 1266.3.1 Pharmacology 1266.3.2 Pharmacokinetics 1276.3.3 Toxicology 1286.4 Physical Characterisation 1296.5 Clinical Studies 1296.6 Conclusion 132References 133Part III Anti-Infective Drug Discoveries 1377 Discovery of Delamanid for the Treatment of Multidrug-Resistant Pulmonary Tuberculosis 139Hidetsugu Tsubouchi, Hirofumi Sasaki, Hiroshi Ishikawa and Makoto Matsumoto7.1 Introduction 1397.2 Synthesis Strategy 1407.3 Synthesis Route 1427.4 Screening Evaluations 1457.4.1 Screening Procedure 1457.4.2 Screening Results 1467.4.3 Selection of a Compound Candidate for Preclinical Tests 1517.5 Preclinical Data of Delamanid 1517.5.1 Antituberculosis Activity 1517.5.2 Mechanism of Action 1537.5.3 Pharmacokinetics 1537.5.4 Genotoxicity and Carcinogenicity 1547.5.5 Preclinical Therapeutic Efficacy 1547.6 Clinical Data of Delamanid 1557.6.1 Clinical Pharmacokinetics 1557.6.2 Drug–Drug Interactions 1567.6.3 Cardiovascular Safety 1567.6.4 Clinical Therapeutic Efficacy 1567.6.5 Other Clinical Trials 1577.7 Future Priorities and Conclusion 158References 1598 Sofosbuvir: The Discovery of a Curative Therapy for the Treatment of Hepatitis C Virus 163Michael J. Sofia8.1 Introduction 1638.2 Discussion 1658.2.1 Target Rationale: HCVNS5BRNA-Dependent RNA Polymerase 1658.2.2 Rationale andDesign of a Liver Targeted Nucleotide Prodrug 1688.2.3 Prodrug Optimization and Preclinical Evaluation 1718.2.4 Prodrug Metabolism 1758.2.5 Clinical Proof of Concept of a Liver Targeted Nucleotide Prodrug 1768.2.6 The Single Diastereomer: Sofosbuvir 1768.2.7 Sofosbuvir Preclinical Profile 1778.2.8 Sofosbuvir Clinical Studies 1798.2.9 Viral Resistance 1828.3 Conclusion 183References 184Part IV Central Nervous System (CNS) Drug Discovery 1899 The Discovery of the Antidepressant Vortioxetine and the Research that Uncovered Its Potential to Treat the Cognitive Dysfunction Associated with Depression 191Benny Bang-Andersen, Christina Kurre Olsen and Connie Sanchéz9.1 Introduction 1919.2 The Discovery of Vortioxetine 1929.3 Clinical Development of Vortioxetine for theTreatment ofMDD 2009.4 UncoveringVortioxetine’s Potential toTreat Cognitive Dysfunction in Patients with MDD 2019.4.1 Early Preclinical Evidence that Differentiated Vortioxetine from Other Antidepressants 2019.4.2 Vortioxetine’s Primary Targets and Their Putative Impact on Cognitive Function – Early Preclinical Data 2029.4.3 Hypothesis-Generating Clinical Study of Vortioxetine’s Effects on Cognitive Symptoms in Elderly Patients with MDD 2039.4.4 Substantiation of a Mechanistic Rationale for the Procognitive Effects of Vortioxetine in Preclinical Models and Its Differentiation from SSRIs and SNRIs 2049.4.5 Confirmation of the Cognitive Benefits of Vortioxetine in Two Large Placebo-Controlled Studies in Adults with MDD 2059.4.6 Additional Translational Evidence of the Effect of Vortioxetine on Brain Activity During Cognitive Performance 2089.5 Conclusion 208References 210Part V Antiulcer Drug Discovery 21510 Discovery of Vonoprazan Fumarate (TAK-438) as a Novel, Potent and Long-Lasting Potassium-Competitive Acid Blocker 217Haruyuki Nishida10.1 Introduction 21710.2 Limitations of PPIs and the Possibility of P-CABs 21810.3 Exploration of Seed Compounds 22010.4 Lead Generation from HTS Hit Compound 1 22010.5 Analysis of SAR and Structure–Toxicity Relationship for Lead Optimization 22310.6 Selection of Vonoprazan Fumarate (TAK-438) as a Candidate Compound 22410.7 Preclinical Study of TAK-438 22610.8 Clinical Study of TAK-438 22810.9 Discussion 22910.10 Conclusion 230References 232Part VI Cross-Therapeutic Drug Discovery (Respiratory Diseases/Anticancer) 23511 Discovery and Development of Nintedanib: A Novel Antiangiogenic and Antifibrotic Agent 237Gerald J. Roth,  Rudolf Binder, Florian Colbatzky, Claudia Dallinger, Rozsa Schlenker-Herceg, Frank Hilberg, Lutz Wollin, John Park, Alexander Pautsch and Rolf Kaiser11.1 Introduction 23711.2 Structure–Activity Relationships of Oxindole Kinase Inhibitors and the Discovery of Nintedanib 23811.3 Structural Research 24411.4 Preclinical Pharmacodynamic Exploration 24611.4.1 Kinase Inhibition Profile of Nintedanib 24611.4.2 Oncology, Disease Pathogenesis and Mechanism of Action 24611.4.3 Idiopathic Pulmonary Fibrosis,Disease Pathogenesis andMechanism of Action 24911.5 Nonclinical Drug Metabolism and Pharmacokinetics 25011.6 Clinical Pharmacokinetics 25111.7 Toxicology 25211.8 Phase III Clinical Data 25311.8.1 Efficacy and Safety of Nintedanib in IPF 25311.8.2 Efficacy and Safety of Nintedanib in NSCLC 25511.9 Other Oncology Studies 25611.10 Conclusions 257References 258Index 267