Successful Drug Discovery, Volume 3

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. Christian Klein is Head of Oncology Programs at the Roche Innovation Center Zurich, specialized in the discovery, validation and preclinical development of antibody based cancer immunotherapies and bispecific antibodies. During his 15 years at Roche he has made major contributions to the development and approval of obinutuzumab, the preclinical development of eight clinical stage bispecific antibodies/immunocytokines that are currently at the clinical stage, as well as the development of Roche's novel proprietary bispecific antibody platforms, e.g., the CrossMAb technology. Wayne E. 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, 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 xviiPart I General Aspects 11 New Trends in Drug Discovery 3Gerd Schnorrenberg1.1 Introduction 31.1.1 Analysis of New Molecular Entities Approved in 2015 31.2 New Trends in NCE Discovery 71.3 Enhanced Lead Generation Strategies 71.3.1 Analogue Approach 91.3.2 High Throughput Screening (HTS) 91.3.3 Structure-Based Design 111.3.4 Virtual Screening 121.3.5 Fragment-Based Lead Discovery 131.3.6 Repositioning 141.3.7 Additional New Trends in Hit/Lead Generation 151.4 Early Assessment of Development Aspects during Drug Discovery 161.4.1 DMPK 171.4.2 Assessment of Physicochemical Parameters 181.4.3 Tolerability Assessment 191.5 New Biological Entities (NBEs) 191.5.1 Antibody Engineering to Reduce Immunogenicity 231.5.2 Progress in Antibody Production and Engineering of Physicochemical Properties 241.5.3 Engineering to Improve Efficacy 251.5.4 New Formats 261.5.4.1 Antibody–Drug Conjugates 261.5.4.2 Bispecific Antibodies 281.6 General Challenges in Drug Discovery 301.7 Summary 31Acknowledgments 31List of Abbreviations 31References 322 Patenting Small and Large Pharmaceutical Molecules 41Uwe Albersmeyer, Ralf Malessa, and Ulrich Storz2.1 The Role of Patents in the Pharmaceutical Industry 412.2 Classification of Active Pharmaceutical Ingredient Grouping 422.3 Patentability Criteria and Patentable Embodiments 432.3.1 Patent Eligibility and Patentability 432.3.2 Patent Eligibility of Molecules 432.3.2.1 Small Molecules and Peptides 442.3.2.2 Molecules Isolated from Nature 442.3.3 Novelty 442.3.3.1 Novelty of Molecules that are More or Less Identical to Molecules from the Human Body 462.3.4 Inventive Step/Non-Obviousness 472.3.5 Patentability Criteria and Patentable Embodiments in Biopharmaceutics 472.3.5.1 Different Types of Biopharmaceutics 472.3.5.2 Monoclonal Antibodies 482.3.5.3 Nucleic Acid-Based Therapeutics 492.4 Patent Term Extensions and Adjustments, Supplementary Protection Certificates, and Data Exclusivity in Biopharmaceutics 492.4.1 Introduction 492.4.2 Patent Lifetime 492.4.2.1 Patent Term Adjustment (PTA) 502.4.2.2 Patent Term Extension (PTE) and Supplementary Protection Certificates (SPC) 502.4.2.3 Pediatric Investigations (EU) 522.4.3 Exclusivity Privileges Related to Regulatory Procedures 532.4.3.1 Data Exclusivity and Market Exclusivity 532.4.3.2 Orphan Drugs 542.5 Patent Lifecycle Management 572.5.1 Formulations and/or Galenics 572.5.2 Combination Products 572.5.3 Second or Higher Medical Indication 582.5.4 New Dosage Regimens 592.5.5 Further Options for Small Molecules 592.5.6 Divisional Applications 602.6 Conclusion 60List of Abbreviations 60References 61Part II Drug Class Studies 653 Kinase Inhibitor Drugs 67Peng Wu and Amit Choudhary3.1 Introduction 673.2 Historical Overview 703.2.1 Before 1980 703.2.2 1980s 703.2.3 1990s 703.2.4 After 2000 723.3 Approved Kinase Inhibitors 723.3.1 FDA-Approved Non-Covalent Small-Molecule Kinase Inhibitors 743.3.1.1 Bcr–Abl Inhibitors 743.3.1.2 ErbB Family Inhibitors 773.3.1.3 VEGFR Family Inhibitors 773.3.1.4 JAK Family Inhibitors 783.3.1.5 ALK Inhibitors 783.3.1.6 MET Inhibitors 783.3.1.7 B-Raf Inhibitors 793.3.1.8 MEK Inhibitors 793.3.1.9 PI3K Inhibitor 793.3.1.10 CDK Inhibitor 803.3.2 FDA Approved Covalent Small Molecule Kinase Inhibitors 803.3.3 FDA-Approved Rapalogs 803.3.4 Other Approved Kinase Inhibitors 813.4 New Directions 823.5 Conclusion 83List of Abbreviations 83References 834 Evolution of Nonsteroidal Androgen Receptor Antagonists 95Arwed Cleve and Duy Nguyen4.1 Introduction 954.2 Flutamide (Eulexin®) 964.3 Nilutamide (Anandron®) 984.4 Bicalutamide (Casodex®) 994.5 Enzalutamide (Xtandi®) 1024.6 Outlook 1064.7 Conclusion 106List of Abbreviations 106References 107Part III Case Studies 1115 Development of T-Cell-Engaging Bispecific Antibody Blinatumomab (Blincyto®) for Treatment of B-Cell Malignancies 113Patrick A. Baeuerle5.1 Introduction 1135.1.1 Brief History of Bispecific Antibodies 1145.1.2 History of T-Cell-Engaging Antibodies 1155.1.3 History and Design of Blinatumomab 1165.1.4 Blinatumomab Mode of Action 1175.1.5 Manufacturing of Blinatumomab 1185.1.6 Clinical Development of Blinatumomab 1185.1.7 Administration of Blinatumomab 1205.1.8 Side Effects of Blinatumomab 1215.2 Discussion 1225.2.1 Other BiTETM Antibodies in Development 1245.2.2 Blinatumomab versus CD19 CAR-T Cell Therapy 1255.3 Summary 126List of Abbreviations 126References 1276 Ceritinib: A Potent ALK Inhibitor for the Treatment of Crizotinib-Resistant Non-Small Cell Lung Cancer Tumors 131Pierre-Yves Michellys6.1 Introduction 1316.2 Drug Design and Strategy 1346.3 Synthesis of Ceritinib 1356.4 In Vitro Evaluation of Ceritinib 1366.5 In Vitro ADME Evaluation of Ceritinib 1376.6 Preclinical Pharmacokinetic Evaluation of Ceritinib 1386.7 In Vivo Evaluation of Ceritinib 1386.8 Evaluation of Ceritinib in Crizotinib-Resistance Mutations 1406.9 Mouse Model of Crizotinib-Resistant Tumors 1416.10 Clinical Phase I Evaluation of Ceritinib 1436.11 Conclusion 146List of Abbreviations 146References 1467 Discovery, Development, and Mechanisms of Action of the Human CD38 Antibody Daratumumab 153Maarten L. Janmaat, Niels W.C.J. van de Donk, Jeroen Lammerts van Bueren, Tahamtan Ahmadi, A. Kate Sasser, Richard K. Jansson, Henk M. Lokhorst, and Paul W.H.I. Parren7.1 Introduction 1537.2 CD38: The Target 1547.2.1 CD38 as a Therapeutic Target 1547.2.2 CD38 Function 1547.2.3 CD38 Expression in Normal Tissue 1557.2.4 CD38 Expression in Cancer 1557.3 Discovery of Daratumumab 1567.4 Daratumumab Combines Multiple Mechanism of Actions 1577.4.1 Complement-Dependent Cytotoxicity (CDC) 1577.4.2 Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) 1587.4.3 Antibody-Dependent Cellular Phagocytosis (ADCP) 1587.4.4 Programmed Cell Death (PCD) 1597.4.5 Enzymatic Modulation 1597.4.6 Immunomodulation 1607.5 Single-Agent Antitumor Activity of Daratumumab in Multiple Myeloma 1607.5.1 Monotherapy Studies with Daratumumab 1637.5.2 Factors That Predict Response to Daratumumab 1647.5.3 Daratumumab in Other Plasma Cell Dyscrasias 1647.5.4 Subcutaneous Delivery of Daratumumab 1657.5.5 Interference of Daratumumab in Clinical Laboratory Assays 1657.6 Daratumumab-Based Combination Therapies in Multiple Myeloma 1667.6.1 Preclinical Combination Studies 1677.6.2 Clinical Combination Studies 1687.7 Potential of Daratumumab Outside Multiple Myeloma 1717.7.1 Other Hematologic Malignancies 1717.7.2 Solid Tumors 1717.7.3 Autoimmune Disorders 1727.8 Conclusions and Future Perspectives 1737.9 Summary 175List of Abbreviations 176References 1788 The Discovery of Obeticholic Acid (OcalivaTM): First-in-Class FXR Agonist 197Roberto Pellicciari, Mark Pruzanski, and Antimo Gioiello8.1 Introduction 1978.2 Bile Acids in Health and Disease 1978.2.1 Structure and Properties of Natural Bile Acids 1978.2.2 Physiology 2008.2.3 Bile Acids as Therapeutic Agents 2028.3 The Early Bile Acid Medicinal Chemistry Program at the University of Perugia 2048.4 The Breakthrough (1999): Bile Acids Are the Endogenous Ligands of the Farnesoid X Receptor (FXR) 2108.5 Discovery of 6α-Ethyl-Chenodeoxycholic Acid (6-ECDCA, INT-747, Obeticholic Acid) 2148.5.1 Design, Synthesis, and Structure–Activity Relationships of C6-Modified CDCA Derivatives 2148.5.2 Scale-Up Synthesis of Obeticholic Acid 2208.6 Properties and Preclinical Studies of Obeticholic Acid 2228.6.1 Physicochemical Properties, Pharmacokinetics, and Metabolism 2228.6.2 OCA in Preclinical Models of Liver Diseases 2258.7 Obeticholic Acid (OcalivaTM) for the Treatment of Primary Biliary Cholangitis (PBC): Phases I–III Clinical Studies to Establish Clinical Efficacy 2288.8 Conclusions and Future Directions 230List of Abbreviations 231References 2329 Discovery and Development of Obinutuzumab (GAZYVA, GAZYVARO), a Glycoengineered Type II Anti-CD20 Antibody for the Treatment of Non-Hodgkin Lymphoma and Chronic Lymphocytic Leukemia 245Christian Klein, Ekkehard Mössner, Marina Bacac, Günter Fingerle-Rowson, and Pablo Umaña9.1 Introduction 2459.2 Preclinical Experience with Obinutuzumab 2469.2.1 Characteristics and Mechanisms of Action of Type I and Type II CD20 Antibodies 2469.2.2 Obinutuzumab Development, Chemistry, and Production 2479.2.3 CD20 Binding by Obinutuzumab 2489.2.4 Complement-Dependent Cytotoxicity 2499.2.5 Direct Cell Death Induction 2499.2.6 FcγR Binding 2499.2.7 Antibody-Dependent Cellular Cytotoxicity and Antibody-Dependent Cellular Phagocytosis 2509.2.8 Whole Blood B-Cell Depletion 2509.2.9 Activity of Single-Agent Obinutuzumab in Human Xenograft Models of B-Cell Lymphoma 2519.2.10 Activity of Obinutuzumab Combined with Chemotherapy and Novel Agents in Human Xenograft Models of B-Cell Lymphoma 2519.2.11 Conclusions from Preclinical Studies 2529.3 Clinical Experience with Obinutuzumab 2539.3.1 Non-Hodgkin Lymphoma 2539.3.1.1 Early Clinical Experience (Phase I/II) 2539.3.1.2 Phase III Studies 2629.3.1.3 Ongoing Clinical Studies of Novel Combinations, Including Chemotherapy-Free Regimens 2699.3.2 Chronic Lymphocytic Leukemia 2709.3.2.1 Early Clinical Experience (Phase I/II) 2709.3.2.2 Phase III Studies 2729.3.2.3 Ongoing Clinical Studies of Novel Combinations, Including Chemotherapy-Free Regimens 2739.3.3 Obinutuzumab in Non-tumor Indications 2739.4 Conclusions 274Acknowledgments 274List of Abbreviations 275References 27610 Omarigliptin (MARIZEVTM, MK-3102) 291Tesfaye Biftu10.1 Introduction 29110.1.1 Discovery of Omarigliptin 29310.1.2 X-ray and Modeling Studies 29710.1.3 Synthesis of Omarigliptin 29810.1.4 In Vitro Pharmacology 30210.1.4.1 In Vivo Pharmacology in Preclinical Species 30210.1.4.2 Pharmacokinetics (PK) in Preclinical Species 30310.1.4.3 Pharmaceutical Properties 30410.1.4.4 Preclinical Safety Pharmacology 30410.1.4.5 Clinical Data 30510.1.5 Add-On Studies 30810.1.5.1 Add-On to Metformin and Sitagliptin 30810.1.5.2 Add-On to Glimepiride 31010.1.5.3 Safety and Tolerability 31110.2 Summary 311List of Abbreviations 312References 31311 Opicapone, a Novel Catechol-O-Methyltranferase Inhibitor (COMT) to Manage the Symptoms of Parkinson’s Disease 319László E. Kiss, Maria João Bonifácio, José Francisco Rocha, and Patrício Soares- da-Silva11.1 Introduction 31911.2 COMT Inhibitors Used in l-DOPA Treatment 32011.3 The Discovery of Opicapone 32211.3.1 Early Pyrazole Analogues 32211.3.2 Modulation of the Central Heterocyclic Core 32511.3.3 Optimization of Oxadiazolyl Nitrocatechols 32711.3.4 Identification of Opicapone 33011.4 Opicapone Preclinical Profile 33211.5 Clinical Studies with Opicapone 33311.5.1 Phase I and Phase II Studies 33311.5.2 Phase III Studies 33411.6 Conclusion 335List of Abbreviations 336References 33612 The Discovery of Osimertinib (TAGRISSOTM): An Irreversible Inhibitor of Activating and T790M Resistant Forms of the Epidermal Growth Factor Receptor Tyrosine Kinase for the Treatment of Non-Small Cell Lung Cancer 341Michael J. Waring12.1 Introduction 34112.2 Discussion 34612.3 Summary 353List of Abbreviations 354Acknowledgment 355References 35513 Discovery of Pitolisant, the First Marketed Histamine H3-Receptor Inverse Agonist/Antagonist for Treating Narcolepsy 359C. Robin Ganellin, Jean-Charles Schwartz, and Holger Stark13.1 Introduction 35913.2 Chemical Background 36013.3 Generation of a Chemical Lead 36213.4 Pharmacological Screening Methods 36613.5 Structure–Activity Optimization 36713.6 Generation of Pitolisant 36913.7 Preclinical Development Studies 37113.8 Clinical Development Studies 37313.9 Conclusion 374Acknowledgment 375List of Abbreviations 375References 37514 Discovery and Development of Safinamide, a New Drug for the Treatment of Parkinson’s Disease 383Paolo Pevarello and Mario Varasi14.1 Introduction 38314.1.1 Parkinson’s Disease 38314.1.2 From James Parkinson to l-Dopa 38514.1.3 Pharmacotherapy of Parkinson’s Disease 38614.2 Discovery of Safinamide 38714.2.1 From Milacemide to Safinamide 38814.2.2 SAR Efforts on 2-Aminoamide Analogues Provide Lead Molecules 39114.2.3 In Vivo Antiepileptic Efficacy Assessment Identifies Safinamide 39514.3 Mechanisms of Action of Safinamide 39614.3.1 Safinamide Inhibits MAO-B 39614.3.2 Safinamide Blocks Voltage-Dependent Sodium Channels (VDSCs) 39814.3.3 Safinamide Modulates Voltage-Dependent Calcium Channels (VDCCs) 39914.3.4 Safinamide Inhibits Glutamate Release 39914.4 Preclinical In Vivo Pharmacological Characterization of Safinamide 39914.4.1 Preclinical Epilepsy Models 40014.4.2 Preclinical PD Models 40114.5 Pharmacokinetics and Metabolism (PKM) 40214.5.1 Preclinical PKM 40214.5.2 Clinical PKM and Safety 40314.6 Clinical Efficacy of Safinamide 40314.6.1 Clinical Studies in Early PD 40314.6.2 Clinical Studies in Advanced PD 40614.6.3 Clinical Trials for Other Indications 40714.7 Safety and Tolerability in Clinical Studies 40814.8 Summary of Clinical Trials and Marketing Authorization 40814.9 Conclusion 408List of Abbreviations 409References 41015 Discovery and Development of Trifluridine/Tipiracil (Lonsurf TM) 417Norihiko Suzuki, Masanobu Ito, and Teiji Takechi15.1 Introduction 41715.2 A Concept to Maximize the Antitumor Effect of 5-FU 41915.3 A Concept to Maximize the Antitumor Effect of FTD 42015.3.1 Medicinal Chemistry: In Vitro and Pharmacokinetic Studies 42015.3.2 Preclinical In vivo Efficacy Studies 42515.4 The Mechanism Underlying the Antitumor Effect of Trifluridine 42715.5 Characterization of the Pharmacologic Effect of FTD/TPI 42915.6 Clinical Pharmacology and Determination of the Optimal Dosing Scheme of FTD/TPI 43015.7 Clinical Efficacy, Safety, and Approval 43215.8 Summary 434List of Abbreviations 435References 435Index 443