Following the successful approach of the previous volumes in the series, inventors and primary developers of successful drugs from both industry and academia tell the story of the drug's discovery and describe the sometimes twisted route from the first drug candidate molecule to the final marketed drug. The 11 case studies selected describe recent drugs ranging across many therapeutic fields and provide a representative cross-section of present-day drug developments. Backed by plenty of data and chemical information, the insight and experience of today's top drug creators makes this one of the most useful training manuals that a junior medicinal chemist may hope to find.
The International Union of Pure and Applied Chemistry has endorsed and sponsored this project because of its high educational merit.
Table of Contents
Preface xvii
Part I General Aspects 1
1 New Trends in Drug Discovery 3
Gerd Schnorrenberg
1.1 Introduction 3
1.1.1 Analysis of New Molecular Entities Approved in 2015 3
1.2 New Trends in NCE Discovery 7
1.3 Enhanced Lead Generation Strategies 7
1.3.1 Analogue Approach 9
1.3.2 High Throughput Screening (HTS) 9
1.3.3 Structure-Based Design 11
1.3.4 Virtual Screening 12
1.3.5 Fragment-Based Lead Discovery 13
1.3.6 Repositioning 14
1.3.7 Additional New Trends in Hit/Lead Generation 15
1.4 Early Assessment of Development Aspects during Drug Discovery 16
1.4.1 DMPK 17
1.4.2 Assessment of Physicochemical Parameters 18
1.4.3 Tolerability Assessment 19
1.5 New Biological Entities (NBEs) 19
1.5.1 Antibody Engineering to Reduce Immunogenicity 23
1.5.2 Progress in Antibody Production and Engineering of Physicochemical Properties 24
1.5.3 Engineering to Improve Efficacy 25
1.5.4 New Formats 26
1.5.4.1 Antibody–Drug Conjugates 26
1.5.4.2 Bispecific Antibodies 28
1.6 General Challenges in Drug Discovery 30
1.7 Summary 31
Acknowledgments 31
List of Abbreviations 31
References 32
2 Patenting Small and Large Pharmaceutical Molecules 41
Uwe Albersmeyer, Ralf Malessa, and Ulrich Storz
2.1 The Role of Patents in the Pharmaceutical Industry 41
2.2 Classification of Active Pharmaceutical Ingredient Grouping 42
2.3 Patentability Criteria and Patentable Embodiments 43
2.3.1 Patent Eligibility and Patentability 43
2.3.2 Patent Eligibility of Molecules 43
2.3.2.1 Small Molecules and Peptides 44
2.3.2.2 Molecules Isolated from Nature 44
2.3.3 Novelty 44
2.3.3.1 Novelty of Molecules that are More or Less Identical to Molecules from the Human Body 46
2.3.4 Inventive Step/Non-Obviousness 47
2.3.5 Patentability Criteria and Patentable Embodiments in Biopharmaceutics 47
2.3.5.1 Different Types of Biopharmaceutics 47
2.3.5.2 Monoclonal Antibodies 48
2.3.5.3 Nucleic Acid-Based Therapeutics 49
2.4 Patent Term Extensions and Adjustments, Supplementary Protection Certificates, and Data Exclusivity in Biopharmaceutics 49
2.4.1 Introduction 49
2.4.2 Patent Lifetime 49
2.4.2.1 Patent Term Adjustment (PTA) 50
2.4.2.2 Patent Term Extension (PTE) and Supplementary Protection Certificates (SPC) 50
2.4.2.3 Pediatric Investigations (EU) 52
2.4.3 Exclusivity Privileges Related to Regulatory Procedures 53
2.4.3.1 Data Exclusivity and Market Exclusivity 53
2.4.3.2 Orphan Drugs 54
2.5 Patent Lifecycle Management 57
2.5.1 Formulations and/or Galenics 57
2.5.2 Combination Products 57
2.5.3 Second or Higher Medical Indication 58
2.5.4 New Dosage Regimens 59
2.5.5 Further Options for Small Molecules 59
2.5.6 Divisional Applications 60
2.6 Conclusion 60
List of Abbreviations 60
References 61
Part II Drug Class Studies 65
3 Kinase Inhibitor Drugs 67
Peng Wu and Amit Choudhary
3.1 Introduction 67
3.2 Historical Overview 70
3.2.1 Before 1980 70
3.2.2 1980s 70
3.2.3 1990s 70
3.2.4 After 2000 72
3.3 Approved Kinase Inhibitors 72
3.3.1 FDA-Approved Non-Covalent Small-Molecule Kinase Inhibitors 74
3.3.1.1 Bcr–Abl Inhibitors 74
3.3.1.2 ErbB Family Inhibitors 77
3.3.1.3 VEGFR Family Inhibitors 77
3.3.1.4 JAK Family Inhibitors 78
3.3.1.5 ALK Inhibitors 78
3.3.1.6 MET Inhibitors 78
3.3.1.7 B-Raf Inhibitors 79
3.3.1.8 MEK Inhibitors 79
3.3.1.9 PI3K Inhibitor 79
3.3.1.10 CDK Inhibitor 80
3.3.2 FDA Approved Covalent Small Molecule Kinase Inhibitors 80
3.3.3 FDA-Approved Rapalogs 80
3.3.4 Other Approved Kinase Inhibitors 81
3.4 New Directions 82
3.5 Conclusion 83
List of Abbreviations 83
References 83
4 Evolution of Nonsteroidal Androgen Receptor Antagonists 95
Arwed Cleve and Duy Nguyen
4.1 Introduction 95
4.2 Flutamide (Eulexin®) 96
4.3 Nilutamide (Anandron®) 98
4.4 Bicalutamide (Casodex®) 99
4.5 Enzalutamide (Xtandi®) 102
4.6 Outlook 106
4.7 Conclusion 106
List of Abbreviations 106
References 107
Part III Case Studies 111
5 Development of T-Cell-Engaging Bispecific Antibody Blinatumomab (Blincyto®) for Treatment of B-Cell Malignancies 113
Patrick A. Baeuerle
5.1 Introduction 113
5.1.1 Brief History of Bispecific Antibodies 114
5.1.2 History of T-Cell-Engaging Antibodies 115
5.1.3 History and Design of Blinatumomab 116
5.1.4 Blinatumomab Mode of Action 117
5.1.5 Manufacturing of Blinatumomab 118
5.1.6 Clinical Development of Blinatumomab 118
5.1.7 Administration of Blinatumomab 120
5.1.8 Side Effects of Blinatumomab 121
5.2 Discussion 122
5.2.1 Other BiTETM Antibodies in Development 124
5.2.2 Blinatumomab versus CD19 CAR-T Cell Therapy 125
5.3 Summary 126
List of Abbreviations 126
References 127
6 Ceritinib: A Potent ALK Inhibitor for the Treatment of Crizotinib-Resistant Non-Small Cell Lung Cancer Tumors 131
Pierre-Yves Michellys
6.1 Introduction 131
6.2 Drug Design and Strategy 134
6.3 Synthesis of Ceritinib 135
6.4 In Vitro Evaluation of Ceritinib 136
6.5 In Vitro ADME Evaluation of Ceritinib 137
6.6 Preclinical Pharmacokinetic Evaluation of Ceritinib 138
6.7 In Vivo Evaluation of Ceritinib 138
6.8 Evaluation of Ceritinib in Crizotinib-Resistance Mutations 140
6.9 Mouse Model of Crizotinib-Resistant Tumors 141
6.10 Clinical Phase I Evaluation of Ceritinib 143
6.11 Conclusion 146
List of Abbreviations 146
References 146
7 Discovery, Development, and Mechanisms of Action of the Human CD38 Antibody Daratumumab 153
Maarten 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. Parren
7.1 Introduction 153
7.2 CD38: The Target 154
7.2.1 CD38 as a Therapeutic Target 154
7.2.2 CD38 Function 154
7.2.3 CD38 Expression in Normal Tissue 155
7.2.4 CD38 Expression in Cancer 155
7.3 Discovery of Daratumumab 156
7.4 Daratumumab Combines Multiple Mechanism of Actions 157
7.4.1 Complement-Dependent Cytotoxicity (CDC) 157
7.4.2 Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) 158
7.4.3 Antibody-Dependent Cellular Phagocytosis (ADCP) 158
7.4.4 Programmed Cell Death (PCD) 159
7.4.5 Enzymatic Modulation 159
7.4.6 Immunomodulation 160
7.5 Single-Agent Antitumor Activity of Daratumumab in Multiple Myeloma 160
7.5.1 Monotherapy Studies with Daratumumab 163
7.5.2 Factors That Predict Response to Daratumumab 164
7.5.3 Daratumumab in Other Plasma Cell Dyscrasias 164
7.5.4 Subcutaneous Delivery of Daratumumab 165
7.5.5 Interference of Daratumumab in Clinical Laboratory Assays 165
7.6 Daratumumab-Based Combination Therapies in Multiple Myeloma 166
7.6.1 Preclinical Combination Studies 167
7.6.2 Clinical Combination Studies 168
7.7 Potential of Daratumumab Outside Multiple Myeloma 171
7.7.1 Other Hematologic Malignancies 171
7.7.2 Solid Tumors 171
7.7.3 Autoimmune Disorders 172
7.8 Conclusions and Future Perspectives 173
7.9 Summary 175
List of Abbreviations 176
References 178
8 The Discovery of Obeticholic Acid (OcalivaTM): First-in-Class FXR Agonist 197
Roberto Pellicciari, Mark Pruzanski, and Antimo Gioiello
8.1 Introduction 197
8.2 Bile Acids in Health and Disease 197
8.2.1 Structure and Properties of Natural Bile Acids 197
8.2.2 Physiology 200
8.2.3 Bile Acids as Therapeutic Agents 202
8.3 The Early Bile Acid Medicinal Chemistry Program at the University of Perugia 204
8.4 The Breakthrough (1999): Bile Acids Are the Endogenous Ligands of the Farnesoid X Receptor (FXR) 210
8.5 Discovery of 6α-Ethyl-Chenodeoxycholic Acid (6-ECDCA, INT-747, Obeticholic Acid) 214
8.5.1 Design, Synthesis, and Structure–Activity Relationships of C6-Modified CDCA Derivatives 214
8.5.2 Scale-Up Synthesis of Obeticholic Acid 220
8.6 Properties and Preclinical Studies of Obeticholic Acid 222
8.6.1 Physicochemical Properties, Pharmacokinetics, and Metabolism 222
8.6.2 OCA in Preclinical Models of Liver Diseases 225
8.7 Obeticholic Acid (OcalivaTM) for the Treatment of Primary Biliary Cholangitis (PBC): Phases I–III Clinical Studies to Establish Clinical Efficacy 228
8.8 Conclusions and Future Directions 230
List of Abbreviations 231
References 232
9 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 245
Christian Klein, Ekkehard Mössner, Marina Bacac, Günter Fingerle-Rowson, and Pablo Umaña
9.1 Introduction 245
9.2 Preclinical Experience with Obinutuzumab 246
9.2.1 Characteristics and Mechanisms of Action of Type I and Type II CD20 Antibodies 246
9.2.2 Obinutuzumab Development, Chemistry, and Production 247
9.2.3 CD20 Binding by Obinutuzumab 248
9.2.4 Complement-Dependent Cytotoxicity 249
9.2.5 Direct Cell Death Induction 249
9.2.6 FcγR Binding 249
9.2.7 Antibody-Dependent Cellular Cytotoxicity and Antibody-Dependent Cellular Phagocytosis 250
9.2.8 Whole Blood B-Cell Depletion 250
9.2.9 Activity of Single-Agent Obinutuzumab in Human Xenograft Models of B-Cell Lymphoma 251
9.2.10 Activity of Obinutuzumab Combined with Chemotherapy and Novel Agents in Human Xenograft Models of B-Cell Lymphoma 251
9.2.11 Conclusions from Preclinical Studies 252
9.3 Clinical Experience with Obinutuzumab 253
9.3.1 Non-Hodgkin Lymphoma 253
9.3.1.1 Early Clinical Experience (Phase I/II) 253
9.3.1.2 Phase III Studies 262
9.3.1.3 Ongoing Clinical Studies of Novel Combinations, Including Chemotherapy-Free Regimens 269
9.3.2 Chronic Lymphocytic Leukemia 270
9.3.2.1 Early Clinical Experience (Phase I/II) 270
9.3.2.2 Phase III Studies 272
9.3.2.3 Ongoing Clinical Studies of Novel Combinations, Including Chemotherapy-Free Regimens 273
9.3.3 Obinutuzumab in Non-tumor Indications 273
9.4 Conclusions 274
Acknowledgments 274
List of Abbreviations 275
References 276
10 Omarigliptin (MARIZEVTM, MK-3102) 291
Tesfaye Biftu
10.1 Introduction 291
10.1.1 Discovery of Omarigliptin 293
10.1.2 X-ray and Modeling Studies 297
10.1.3 Synthesis of Omarigliptin 298
10.1.4 In Vitro Pharmacology 302
10.1.4.1 In Vivo Pharmacology in Preclinical Species 302
10.1.4.2 Pharmacokinetics (PK) in Preclinical Species 303
10.1.4.3 Pharmaceutical Properties 304
10.1.4.4 Preclinical Safety Pharmacology 304
10.1.4.5 Clinical Data 305
10.1.5 Add-On Studies 308
10.1.5.1 Add-On to Metformin and Sitagliptin 308
10.1.5.2 Add-On to Glimepiride 310
10.1.5.3 Safety and Tolerability 311
10.2 Summary 311
List of Abbreviations 312
References 313
11 Opicapone, a Novel Catechol-O-Methyltranferase Inhibitor (COMT) to Manage the Symptoms of Parkinson’s Disease 319
László E. Kiss, Maria João Bonifácio, José Francisco Rocha, and Patrício Soares- da-Silva
11.1 Introduction 319
11.2 COMT Inhibitors Used in l-DOPA Treatment 320
11.3 The Discovery of Opicapone 322
11.3.1 Early Pyrazole Analogues 322
11.3.2 Modulation of the Central Heterocyclic Core 325
11.3.3 Optimization of Oxadiazolyl Nitrocatechols 327
11.3.4 Identification of Opicapone 330
11.4 Opicapone Preclinical Profile 332
11.5 Clinical Studies with Opicapone 333
11.5.1 Phase I and Phase II Studies 333
11.5.2 Phase III Studies 334
11.6 Conclusion 335
List of Abbreviations 336
References 336
12 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 341
Michael J. Waring
12.1 Introduction 341
12.2 Discussion 346
12.3 Summary 353
List of Abbreviations 354
Acknowledgment 355
References 355
13 Discovery of Pitolisant, the First Marketed Histamine H3-Receptor Inverse Agonist/Antagonist for Treating Narcolepsy 359
C. Robin Ganellin, Jean-Charles Schwartz, and Holger Stark
13.1 Introduction 359
13.2 Chemical Background 360
13.3 Generation of a Chemical Lead 362
13.4 Pharmacological Screening Methods 366
13.5 Structure–Activity Optimization 367
13.6 Generation of Pitolisant 369
13.7 Preclinical Development Studies 371
13.8 Clinical Development Studies 373
13.9 Conclusion 374
Acknowledgment 375
List of Abbreviations 375
References 375
14 Discovery and Development of Safinamide, a New Drug for the Treatment of Parkinson’s Disease 383
Paolo Pevarello and Mario Varasi
14.1 Introduction 383
14.1.1 Parkinson’s Disease 383
14.1.2 From James Parkinson to l-Dopa 385
14.1.3 Pharmacotherapy of Parkinson’s Disease 386
14.2 Discovery of Safinamide 387
14.2.1 From Milacemide to Safinamide 388
14.2.2 SAR Efforts on 2-Aminoamide Analogues Provide Lead Molecules 391
14.2.3 In Vivo Antiepileptic Efficacy Assessment Identifies Safinamide 395
14.3 Mechanisms of Action of Safinamide 396
14.3.1 Safinamide Inhibits MAO-B 396
14.3.2 Safinamide Blocks Voltage-Dependent Sodium Channels (VDSCs) 398
14.3.3 Safinamide Modulates Voltage-Dependent Calcium Channels (VDCCs) 399
14.3.4 Safinamide Inhibits Glutamate Release 399
14.4 Preclinical In Vivo Pharmacological Characterization of Safinamide 399
14.4.1 Preclinical Epilepsy Models 400
14.4.2 Preclinical PD Models 401
14.5 Pharmacokinetics and Metabolism (PKM) 402
14.5.1 Preclinical PKM 402
14.5.2 Clinical PKM and Safety 403
14.6 Clinical Efficacy of Safinamide 403
14.6.1 Clinical Studies in Early PD 403
14.6.2 Clinical Studies in Advanced PD 406
14.6.3 Clinical Trials for Other Indications 407
14.7 Safety and Tolerability in Clinical Studies 408
14.8 Summary of Clinical Trials and Marketing Authorization 408
14.9 Conclusion 408
List of Abbreviations 409
References 410
15 Discovery and Development of Trifluridine/Tipiracil (Lonsurf TM) 417
Norihiko Suzuki, Masanobu Ito, and Teiji Takechi
15.1 Introduction 417
15.2 A Concept to Maximize the Antitumor Effect of 5-FU 419
15.3 A Concept to Maximize the Antitumor Effect of FTD 420
15.3.1 Medicinal Chemistry: In Vitro and Pharmacokinetic Studies 420
15.3.2 Preclinical In vivo Efficacy Studies 425
15.4 The Mechanism Underlying the Antitumor Effect of Trifluridine 427
15.5 Characterization of the Pharmacologic Effect of FTD/TPI 429
15.6 Clinical Pharmacology and Determination of the Optimal Dosing Scheme of FTD/TPI 430
15.7 Clinical Efficacy, Safety, and Approval 432
15.8 Summary 434
List of Abbreviations 435
References 435
Index 443
