Successful Drug Discovery, Volume 4

János Fischer, PhD, is a Senior Research Scientist at Richter Plc., Budapest, Hungary, and is Member of the Subcommittee on Drug Discovery and Development of IUPAC. Christian Klein, PhD, is Department Head Cancer Immunotherapy Discovery 3 and Site Head at the Roche Innovation Center Zurich, specialized in the discovery, validation, and preclinical development of antibody based cancer immunotherapies and bispecific antibodies. Wayne E. Childers, PhD, is Associate Professor of Pharmaceutical Sciences at Temple University School of Pharmacy, Philadelphia, USA.

• Advisory Board Members xiPreface xiiiPart I General Aspects 11 Trends in Peptide Therapeutics 3Florence M. Brunel, Fa Liu, and John P. Mayer1.1 Introduction 31.2 Peptides in Metabolic Diseases 41.2.1 Insulins 41.2.2 Glucagon]like Peptide]1 61.2.3 Glucagon 81.2.4 Combination Therapies 81.3 Peptide Antibiotics 91.3.1 Non]ribosomally Synthesized 91.3.2 Ribosomally Synthesized 111.4 Peptides in Cancer 121.4.1 Luteinizing Hormone Releasing Hormone 121.4.2 Somatostatin 131.4.3 Peptide–Drug Conjugates 141.4.4 Cancer Vaccines 151.5 Peptides in Bone Diseases 161.5.1 Calcitonin 161.5.2 Parathyroid Hormone (PTH) (1–34) and (1–84) 171.5.3 Parathyroid Hormone Related Protein 181.5.4 Incretin Peptides 191.5.5 Bone Morphogenic Protein]Derived Peptides 191.6 Peptides in Gastrointestinal Diseases 191.6.1 Glucagon]like Peptide]2 191.6.2 Guanylate Cyclase]C Agonists 201.7 Emerging Trends in Peptide Drug Discovery 221.7.1 Cell]Penetrating Peptides 221.7.2 Macrocyclic Peptides 231.8 Summary 23Acknowledgment 24List of Abbreviations 24References25Biographies 342 Physicochemical Parameters of Recently Approved Oral Drugs 35Andreas Ritzén and Laurent David2.1 Introduction 352.2 FDA]Approved Drugs 2007–2017 362.2.1 Conclusions 402.3 Polar Surface Area in bRo5 Territory 422.3.1 Finding Chameleons with Molecular Dynamics 442.3.2 Conclusions 482.3.3 Methods 49List of Abbreviations 50References 51Biographies 52Part II Drug Class Studies 553 Antibody–Drug Conjugates: Empowering Antibodies for the Fight Against Cancer 57Caroline Denevault]Sabourin, Francesca Bryden, Marie]Claude Viaud]Massuard, and Nicolas Joubert3.1 Introduction 573.2 First Generation ADCs 583.2.1 Molecular Design 583.2.2 Mechanism of Action 603.2.3 Therapeutic Applications 603.2.4 Adverse Effects 603.3 Second Generation ADCs 623.3.1 Molecular Design 623.3.2 Mechanism of Action 633.3.3 Therapeutic Applications 673.3.4 Adverse Effects 673.4 Toward Next Generation ADCs 683.4.1 Site]Specific ADCs 693.4.2 New Formats of Immunoconjugates 703.4.3 ADC with New Payloads 743.5 Summary 76List of Abbreviations 76References 77Biographies 814 Dopamine D2 Partial Agonists – Discovery, Evolution, and Therapeutic Potential 83Marlene Jacobson, Wayne Childers, and Magid Abou]Gharbia4.1 Introduction 834.2 Dopamine and Dopamine Receptors 834.2.1 Functional Selectivity and Biased Ligand Signaling 864.3 Schizophrenia and Earlier Antipsychotic Agents 864.4 Dopamine Partial Agonism 884.5 D2 Partial Agonists 894.5.1 Dopamine]like Scaffolds – The “Classical” Pharmacophore 894.5.2 Non]dopamine]like Scaffolds – The “Nonclassical” Pharmacophore 914.5.3 Compounds Related to Bifeprunox 924.5.4 Methylaminochroman Scaffold – Aplindore 944.5.5 D2 Partial Agonist Drug Discovery in the Wake of the Marketed Drugs 954.5.5.1 D2 Partial Agonists Discovered Using Traditional D2 Functional Screening 964.5.5.2 Bivalent Ligands 984.5.5.3 β]Arrestin]Biased D2 Partial Agonists 984.5.5.4 G]protein]Biased D2 Partial Agonists 994.5.6 Arylpiperazines and the Discovery of Aripiprazole and Brexpiprazole 1014.5.7 The Road Leading to Cariprazine 1024.6 Marketed D2 Partial Agonist Antipsychotics 1034.6.1 Aripiprazole (Abilify®) 1044.6.1.1 History 1054.6.1.2 Synthesis 1054.6.1.3 Drug Substance 1054.6.1.4 Pharmacology 1054.6.1.5 Functional Selectivity and Biased Ligand Signaling 1074.6.1.6 Pharmacokinetics and Metabolism 1074.6.1.7 Clinical Data 1074.6.2 Brexpiprazole (Rexulti®) 1084.6.2.1 History 1084.6.2.2 Synthesis 1084.6.2.3 Drug Substance 1094.6.2.4 Pharmacology 1094.6.2.5 Functional Selectivity and Biased Ligand Signaling 1104.6.2.6 Pharmacokinetics and Metabolism 1104.6.2.7 Clinical Data 1104.6.3 Cariprazine (Vraylar®) 1114.6.3.1 History 1114.6.3.2 Synthesis 1124.6.3.3 Drug Substance 1124.6.3.4 Pharmacology 1124.6.3.5 Functional Selectivity and Biased Ligand Signaling 1134.6.3.6 Pharmacokinetics 1134.6.3.7 Clinical Data 1144.7 Conclusions 115List of Abbreviations 116References 117Biographies 129Part III Case Studies 1315 Discovery of Etelcalcetide for the Treatment of Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease 133Amos Baruch and Derek Maclean5.1 Introduction 1335.2 Compound Design and Structure–Activity Relationships 1355.2.1 Optimization of the Cationic Charge 1355.2.2 Alanine Scan of dCR6 1365.2.3 Double Alanine Scan of dCR6 1385.2.4 SAR of Alanine Residues in Ac]carrrar]NH2 and Ac]crrarar]NH2 1385.2.5 Importance of the Thiol Residue 1405.2.6 Thiol Conjugates – Selection of Etelcalcetide 1405.3 Preclinical Studies 1415.4 Mechanism of Action of Etelcalcetide 1445.5 Clinical Studies 1455.6 Summary 149Acknowledgments 149List of Abbreviations 149References 150Biographies 1536 Development of Lenvatinib Mesylate, an Angiogenesis Inhibitor Targeting VEGF and FGF Receptors 155Akihiko Tsuruoka, Yasuhiro Funahashi, Junji Matsui, and Tomohiro Matsushima6.1 Introduction 1556.2 Recent Progress in the Development of Molecular Targeted Anticancer Agents 1556.3 Tumor Angiogenesis 1566.4 Development of Resistance to VEGF]Targeting Drugs 1566.5 Discovery of Lenvatinib, a Drug Targeting VEGFR and FGFR 1576.6 Inhibition of Kinase Activity by Lenvatinib and Discovery of the Novel Type V Kinase]Binding Mode 1586.7 Antitumor Effects of Lenvatinib in Human Thyroid Cancer Cell Lines 1616.8 Antitumor Effects of Lenvatinib in Human Renal Cell Cancer Cell Lines and its Mechanism of Action 1626.9 Conclusions and Perspectives 162List of Abbreviations 163References 164Biographies 1677 Ocrelizumab: A New Generation of anti CD20 mAb for Treatment of Multiple Sclerosis 169Andrew C. Chan, Paul Brunetta, and Peter Chin7.1 Introduction: B Cells Play Critical Roles in Immunity 1697.2 Role of B Cells in Autoimmunity 1727.3 CD20] Targeting Therapeutic Antibodies 1737.4 Rituximab: the First Anti]CD20 mAb Experience in Autoimmunity 1767.5 Effects of Rituximab on Antibodies and Autoantibodies 1787.6 Rituximab in AAV and Other Autoimmune Disorders 1787.7 Beginnings of Ocrelizumab 1797.8 Multiple Sclerosis 1807.9 Multiple Sclerosis Disease Pathogenesis 1817.10 Rituximab: The First Anti]CD20 mAb Experience in Multiple Sclerosis 1837.10.1 HERMES Junior 1837.10.2 HERMES 1837.10.3 OLYMPUS 1847.11 Ocrelizumab in Multiple Sclerosis 1847.11.1 OPERA 1857.11.2 ORATORIO 1867.12 The Conundrum of B Cells in Multiple Sclerosis 1877.13 Final Comments 187List of Abbreviations 188Acknowledgments 189References 189Biographies 1988 The Story of Rucaparib (Rubraca) 201Bernard T. Golding8.1 Introduction 2018.2 Benzoxazole]/Benzimidazole]carboxamides and Quinazolinones 2058.3 The Road to Rucaparib/Rubraca 2128.4 The Emergence of Single]Agent Therapy 2168.5 Clinical Studies 2178.6 Conclusion 218Acknowledgments 218References 219Biography 2239 Discovery and Development of Venetoclax, a Selective Antagonist of BCL2 225Wayne J. Fairbrother, Joel D. Leverson, Deepak Sampath, and Andrew J. Souers9.1 Introduction 2259.2 Discovery of Venetoclax – Structure]Based Design 2279.3 Preclinical Studies 2329.3.1 Mechanism of Action 2329.3.2 Predictive Biomarkers of Venetoclax Sensitivity 2339.3.3 Efficacy of Venetoclax as Monotherapy and in Combination with Targeted Agents or Chemotherapeutics 2349.4 Clinical Studies 236List of Abbreviations 238References 239Biographies 244Index 247