In this fourth volume in the series, inventors and primary developers of drugs that made it to the market continue telling the story of the drugs? discovery and development, and discuss the sometimes twisted route from the first drug candidate molecule to the final marketed one. Beginning with a general section addressing overarching topics for drug discovery, the book offers seven chapters that feature selected case studies describing recently introduced drugs or drug classes. These include small molecule drugs as well as biopharmaceuticals and range across different therapeutic fields. Together, they provide a representative cross-section of the present-day drug development effort.
Successful Drug Discovery: Volume 4 covers trends in peptide-based drug discovery and the physicochemical properties of recently approved oral drugs. The section on drug class studies looks at antibody-drug conjugates and the discovery, evolution, and therapeutic potential of dopamine partial agonists. Featured case studies examine the discovery of Etelcalcetide for the treatment of secondary hyper-parathyroidism in patients with chronic kidney disease; the development of Lenvatinib Mesylate; the discovery and development of Venetoclax; and more.
-Focuses on recently introduced drugs that have not been featured in any textbooks or general references, including Ocrelizumab, a new generation of anti-CD-20 mAb for the treatment of multiple sclerosis, and Venetoclax, a selective antagonist of BCL-2
-Features personal experiences of successful drug developers from industry and academia
-Endorsed and supported by the International Union of Pure and Applied Chemistry (IUPAC)
Successful Drug Discovery: Volume 4 provides a fascinating and informative look into the process of drug discovery and would be a great reference for those in the pharmaceutical industry, organic and pharmaceutical chemists, and lecturers in pharmacy.
Table of Contents
Advisory Board Members xi
Preface xiii
Part I General Aspects 1
1 Trends in Peptide Therapeutics 3
Florence M. Brunel, Fa Liu, and John P. Mayer
1.1 Introduction 3
1.2 Peptides in Metabolic Diseases 4
1.2.1 Insulins 4
1.2.2 Glucagon‐like Peptide‐1 6
1.2.3 Glucagon 8
1.2.4 Combination Therapies 8
1.3 Peptide Antibiotics 9
1.3.1 Non‐ribosomally Synthesized 9
1.3.2 Ribosomally Synthesized 11
1.4 Peptides in Cancer 12
1.4.1 Luteinizing Hormone Releasing Hormone 12
1.4.2 Somatostatin 13
1.4.3 Peptide-Drug Conjugates 14
1.4.4 Cancer Vaccines 15
1.5 Peptides in Bone Diseases 16
1.5.1 Calcitonin 16
1.5.2 Parathyroid Hormone (PTH) (1-34) and (1-84) 17
1.5.3 Parathyroid Hormone Related Protein 18
1.5.4 Incretin Peptides 19
1.5.5 Bone Morphogenic Protein‐Derived Peptides 19
1.6 Peptides in Gastrointestinal Diseases 19
1.6.1 Glucagon‐like Peptide‐2 19
1.6.2 Guanylate Cyclase‐C Agonists 20
1.7 Emerging Trends in Peptide Drug Discovery 22
1.7.1 Cell‐Penetrating Peptides 22
1.7.2 Macrocyclic Peptides 23
1.8 Summary 23
Acknowledgment 24
List of Abbreviations 24
References25
Biographies 34
2 Physicochemical Parameters of Recently Approved Oral Drugs 35
Andreas Ritzén and Laurent David
2.1 Introduction 35
2.2 FDA‐Approved Drugs 2007-2017 36
2.2.1 Conclusions 40
2.3 Polar Surface Area in bRo5 Territory 42
2.3.1 Finding Chameleons with Molecular Dynamics 44
2.3.2 Conclusions 48
2.3.3 Methods 49
List of Abbreviations 50
References 51
Biographies 52
Part II Drug Class Studies 55
3 Antibody-Drug Conjugates: Empowering Antibodies for the Fight Against Cancer 57
Caroline Denevault‐Sabourin, Francesca Bryden, Marie‐Claude Viaud‐Massuard, and Nicolas Joubert
3.1 Introduction 57
3.2 First Generation ADCs 58
3.2.1 Molecular Design 58
3.2.2 Mechanism of Action 60
3.2.3 Therapeutic Applications 60
3.2.4 Adverse Effects 60
3.3 Second Generation ADCs 62
3.3.1 Molecular Design 62
3.3.2 Mechanism of Action 63
3.3.3 Therapeutic Applications 67
3.3.4 Adverse Effects 67
3.4 Toward Next Generation ADCs 68
3.4.1 Site‐Specific ADCs 69
3.4.2 New Formats of Immunoconjugates 70
3.4.3 ADC with New Payloads 74
3.5 Summary 76
List of Abbreviations 76
References 77
Biographies 81
4 Dopamine D2 Partial Agonists - Discovery, Evolution, and Therapeutic Potential 83
Marlene Jacobson, Wayne Childers, and Magid Abou‐Gharbia
4.1 Introduction 83
4.2 Dopamine and Dopamine Receptors 83
4.2.1 Functional Selectivity and Biased Ligand Signaling 86
4.3 Schizophrenia and Earlier Antipsychotic Agents 86
4.4 Dopamine Partial Agonism 88
4.5 D2 Partial Agonists 89
4.5.1 Dopamine‐like Scaffolds - The “Classical” Pharmacophore 89
4.5.2 Non‐dopamine‐like Scaffolds - The “Nonclassical” Pharmacophore 91
4.5.3 Compounds Related to Bifeprunox 92
4.5.4 Methylaminochroman Scaffold - Aplindore 94
4.5.5 D2 Partial Agonist Drug Discovery in the Wake of the Marketed Drugs 95
4.5.5.1 D2 Partial Agonists Discovered Using Traditional D2 Functional Screening 96
4.5.5.2 Bivalent Ligands 98
4.5.5.3 β‐Arrestin‐Biased D2 Partial Agonists 98
4.5.5.4 G‐protein‐Biased D2 Partial Agonists 99
4.5.6 Arylpiperazines and the Discovery of Aripiprazole and Brexpiprazole 101
4.5.7 The Road Leading to Cariprazine 102
4.6 Marketed D2 Partial Agonist Antipsychotics 103
4.6.1 Aripiprazole (Abilify®) 104
4.6.1.1 History 105
4.6.1.2 Synthesis 105
4.6.1.3 Drug Substance 105
4.6.1.4 Pharmacology 105
4.6.1.5 Functional Selectivity and Biased Ligand Signaling 107
4.6.1.6 Pharmacokinetics and Metabolism 107
4.6.1.7 Clinical Data 107
4.6.2 Brexpiprazole (Rexulti®) 108
4.6.2.1 History 108
4.6.2.2 Synthesis 108
4.6.2.3 Drug Substance 109
4.6.2.4 Pharmacology 109
4.6.2.5 Functional Selectivity and Biased Ligand Signaling 110
4.6.2.6 Pharmacokinetics and Metabolism 110
4.6.2.7 Clinical Data 110
4.6.3 Cariprazine (Vraylar®) 111
4.6.3.1 History 111
4.6.3.2 Synthesis 112
4.6.3.3 Drug Substance 112
4.6.3.4 Pharmacology 112
4.6.3.5 Functional Selectivity and Biased Ligand Signaling 113
4.6.3.6 Pharmacokinetics 113
4.6.3.7 Clinical Data 114
4.7 Conclusions 115
List of Abbreviations 116
References 117
Biographies 129
Part III Case Studies 131
5 Discovery of Etelcalcetide for the Treatment of Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease 133
Amos Baruch and Derek Maclean
5.1 Introduction 133
5.2 Compound Design and Structure-Activity Relationships 135
5.2.1 Optimization of the Cationic Charge 135
5.2.2 Alanine Scan of dCR6 136
5.2.3 Double Alanine Scan of dCR6 138
5.2.4 SAR of Alanine Residues in Ac‐carrrar‐NH2 and Ac‐crrarar‐NH2 138
5.2.5 Importance of the Thiol Residue 140
5.2.6 Thiol Conjugates - Selection of Etelcalcetide 140
5.3 Preclinical Studies 141
5.4 Mechanism of Action of Etelcalcetide 144
5.5 Clinical Studies 145
5.6 Summary 149
Acknowledgments 149
List of Abbreviations 149
References 150
Biographies 153
6 Development of Lenvatinib Mesylate, an Angiogenesis Inhibitor Targeting VEGF and FGF Receptors 155
Akihiko Tsuruoka, Yasuhiro Funahashi, Junji Matsui, and Tomohiro Matsushima
6.1 Introduction 155
6.2 Recent Progress in the Development of Molecular Targeted Anticancer Agents 155
6.3 Tumor Angiogenesis 156
6.4 Development of Resistance to VEGF‐Targeting Drugs 156
6.5 Discovery of Lenvatinib, a Drug Targeting VEGFR and FGFR 157
6.6 Inhibition of Kinase Activity by Lenvatinib and Discovery of the Novel Type V Kinase‐Binding Mode 158
6.7 Antitumor Effects of Lenvatinib in Human Thyroid Cancer Cell Lines 161
6.8 Antitumor Effects of Lenvatinib in Human Renal Cell Cancer Cell Lines and its Mechanism of Action 162
6.9 Conclusions and Perspectives 162
List of Abbreviations 163
References 164
Biographies 167
7 Ocrelizumab: A New Generation of anti CD20 mAb for Treatment of Multiple Sclerosis 169
Andrew C. Chan, Paul Brunetta, and Peter Chin
7.1 Introduction: B Cells Play Critical Roles in Immunity 169
7.2 Role of B Cells in Autoimmunity 172
7.3 CD20‐ Targeting Therapeutic Antibodies 173
7.4 Rituximab: the First Anti‐CD20 mAb Experience in Autoimmunity 176
7.5 Effects of Rituximab on Antibodies and Autoantibodies 178
7.6 Rituximab in AAV and Other Autoimmune Disorders 178
7.7 Beginnings of Ocrelizumab 179
7.8 Multiple Sclerosis 180
7.9 Multiple Sclerosis Disease Pathogenesis 181
7.10 Rituximab: The First Anti‐CD20 mAb Experience in Multiple Sclerosis 183
7.10.1 HERMES Junior 183
7.10.2 HERMES 183
7.10.3 OLYMPUS 184
7.11 Ocrelizumab in Multiple Sclerosis 184
7.11.1 OPERA 185
7.11.2 ORATORIO 186
7.12 The Conundrum of B Cells in Multiple Sclerosis 187
7.13 Final Comments 187
List of Abbreviations 188
Acknowledgments 189
References 189
Biographies 198
8 The Story of Rucaparib (Rubraca) 201
Bernard T. Golding
8.1 Introduction 201
8.2 Benzoxazole‐/Benzimidazole‐carboxamides and Quinazolinones 205
8.3 The Road to Rucaparib/Rubraca 212
8.4 The Emergence of Single‐Agent Therapy 216
8.5 Clinical Studies 217
8.6 Conclusion 218
Acknowledgments 218
References 219
Biography 223
9 Discovery and Development of Venetoclax, a Selective Antagonist of BCL 2 225
Wayne J. Fairbrother, Joel D. Leverson, Deepak Sampath, and Andrew J. Souers
9.1 Introduction 225
9.2 Discovery of Venetoclax - Structure‐Based Design 227
9.3 Preclinical Studies 232
9.3.1 Mechanism of Action 232
9.3.2 Predictive Biomarkers of Venetoclax Sensitivity 233
9.3.3 Efficacy of Venetoclax as Monotherapy and in Combination with Targeted Agents or Chemotherapeutics 234
9.4 Clinical Studies 236
List of Abbreviations 238
References 239
Biographies 244
Index 247
