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. He is the author of some 100 patents and scientific publications. In 2004, he was elected as a Titular member of the Chemistry and Human Health Division of IUPAC. He received an honorary professorship at the Technical University of Budapest.David Rotella is the Margaret and Herman Sokol Professor of Medicinal Chemistry at Montclair State University. He earned a B.S. Pharm. degree at the University of Pittsburgh (1981) and a Ph.D. (1985) at The Ohio State University with Donald. T. Witiak. After postdoctoral studies in organic chemistry at Penn State University with Ken S. Feldman, he became an assistant professor at the University of Mississippi. Before accepting his current position he worked at Cephalon, Bristol-Myers, Lexicon and Wyeth where he was involved in neurodegeneration, schizophrenia, cardiovascular and metabolic disease drug discovery projects.

"In summary, this book provides a diverse set of insights into successful drug discovery cases and concepts. It is highly valuable both to support teaching and as a motivating read for medicinal chemists in academia and industry." (ChemMedChem, 1 October 2015)"Because of the manner in which this book combines basic broad concepts (Section I), a detailed overview of an class of molecules (Section II), and narrowly focused case studies (Section III), it would be a valuable addition to the library of any group doing drug discovery and development." (Chemistry International 2016)

• Preface XIIIList of Contributors XVIIPart I General Aspects 11 Serendipitous Target-Based Drug Discoveries 3Janos Fischer and David P. Rotella1.1 Introduction 31.2 Recent Examples of Target-Based Drug Discovery 41.3 Serendipitous Target-Based Drug Discoveries 71.4 Drospirenone (Contraceptive with Anti-aldosterone Activity) 71.5 Escitalopram (Selective Serotonin Reuptake Inhibitor Antidepressant) 91.6 Ezetimibe (Inhibitor of Cholesterol Absorption) 111.7 Lamotrigine (Discovery of a Standalone Drug for the Treatment of Epilepsy) 131.8 Omeprazole (Proton Pump Inhibitor Acid-Suppressive Agent) 151.9 Outlook 17Acknowledgments 17List of Abbreviations 17References 182 Drug Discoveries and Molecular Mechanism of Action 19David C. Swinney2.1 Introduction 192.2 Mechanistic Paradox 192.3 Molecular Mechanism of Action 202.4 How MMOAs were Discovered 252.5 Case Study: Artemisinin 302.6 Summary 31List of Abbreviations 32References 32Part II Drug Class 353 Insulin Analogs – Improving the Therapy of Diabetes 37John M. Beals3.1 Introduction 373.2 Pharmacology and Insulin Analogs 383.3 Chemical Description 393.4 Rapid-Acting Insulin Analogs (Prandial or Bolus Insulin) 413.5 Long-Acting Insulin Analog Formulations (Basal Insulin) 483.6 Conclusions and Future Considerations 54List of Abbreviations 55References 55Part III Case Histories 614 The Discovery of Stendra™(Avanafil) for the Treatment of Erectile Dysfunction 63Koichiro Yamada, Toshiaki Sakamoto, Kenji Omori, and Kohei Kikkawa4.1 Introduction 634.2 Discovery of Avanafil 654.4 Clinical Studies of Avanafil 814.5 Conclusion 83List of Abbreviations 83References 835 Dapagliflozin, A Selective SGLT2 Inhibitor for Treatment of Diabetes 87William N.Washburn5.1 Introduction 875.2 Role of SGLT2 Transporters in Renal Function 885.3 O-Glucoside SGLT2 Inhibitors 895.4 m-Diarylmethane C-Glucosides 975.5 Profiling Studies with Dapagliflozin 1055.6 Clinical Studies with Dapagliflozin 1085.7 Summary 108List of Abbreviations 109References 1106 Elvitegravir, A New HIV-1 Integrase Inhibitor for Antiretroviral Therapy 113Hisashi Shinkai6.1 Introduction 1136.2 Discovery of Elvitegravir 1146.3 Conclusion 121List of Abbreviations 123References 1237 Discovery of Linagliptin for the Treatment of Type 2 Diabetes Mellitus 129Matthias Eckhardt, Thomas Klein, Herbert Nar, and Sandra Thiemann7.1 Introduction 1297.2 Discovery of Linagliptin – HighThroughput Screening Hit Optimization 1307.3 Rationalization of DPP-4 Inhibition Potency by Crystal Structure Analysis and Studies of Binding Kinetics 1397.4 Basic Physicochemical, Pharmacological, and Kinetic Characteristics 1417.5 Preclinical Studies 1437.6 Clinical Studies 1467.7 Conclusion 151List of Abbreviations 151References 1528 The Discovery of Alimta (Pemetrexed) 157Edward C. TaylorList of Abbreviations 175References 1769 Perampanel: A Novel, Noncompetitive AMPA Receptor Antagonist for the Treatment of Epilepsy 181Shigeki Hibi9.1 Introduction 1819.2 Seeds Identification by High Throughput Screening (HTS) Assays 1839.3 Structure and Activity Relationship (SAR) Study Starting from the Unique Structure of Seed Compounds 1849.4 Pharmacological Properties of Perampanel; Selection for Clinical Development 1879.5 Clinical Development of Perampanel 1899.6 Conclusion 190List of Abbreviations 190References 19110 Discovery and Development of Telaprevir (Incivek™) – A Protease Inhibitor to Treat Hepatitis C Infection 195Bhisetti G. Rao, Mark A. Murcko, Mark J. Tebbe, and Ann D. Kwong10.1 Introduction 19510.2 Discussion 19710.3 Summary 207List of Abbreviations 208References 20911 Antibody–Drug Conjugates: Design and Development of Trastuzumab Emtansine (T-DM1) 213Sandhya Girish, Gail D. Lewis Phillips, Fredric S. Jacobson, Jagath R. Junutula, and Ellie Guardino11.1 Introduction 21311.2 Molecular Design of T-DM1 21411.3 Strategies for Bioanalysis 21611.4 Strategies for Chemistry and Manufacturing Control 21811.5 Nonclinical Development 21911.6 Clinical Pharmacology 22011.7 Clinical Trials and Approval 22211.8 Summary 224List of Abbreviations 225References 226Index 231

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. He is the author of some 100 patents and scientific publications. In 2004, he was elected as a Titular member of the Chemistry and Human Health Division of IUPAC. He received an honorary professorship at the Technical University of Budapest.David Rotella is the Margaret and Herman Sokol Professor of Medicinal Chemistry at Montclair State University. He earned a B.S. Pharm. degree at the University of Pittsburgh (1981) and a Ph.D. (1985) at The Ohio State University with Donald. T. Witiak. After postdoctoral studies in organic chemistry at Penn State University with Ken S. Feldman, he became an assistant professor at the University of Mississippi. Before accepting his current position he worked at Cephalon, Bristol-Myers, Lexicon and Wyeth where he was involved in neurodegeneration, schizophrenia, cardiovascular and metabolic disease drug discovery projects.

"In summary, this book provides a diverse set of insights into successful drug discovery cases and concepts. It is highly valuable both to support teaching and as a motivating read for medicinal chemists in academia and industry." (ChemMedChem, 1 October 2015)"Because of the manner in which this book combines basic broad concepts (Section I), a detailed overview of an class of molecules (Section II), and narrowly focused case studies (Section III), it would be a valuable addition to the library of any group doing drug discovery and development." (Chemistry International 2016)

• Preface XIIIList of Contributors XVIIPart I General Aspects 11 Serendipitous Target-Based Drug Discoveries 3Janos Fischer and David P. Rotella1.1 Introduction 31.2 Recent Examples of Target-Based Drug Discovery 41.3 Serendipitous Target-Based Drug Discoveries 71.4 Drospirenone (Contraceptive with Anti-aldosterone Activity) 71.5 Escitalopram (Selective Serotonin Reuptake Inhibitor Antidepressant) 91.6 Ezetimibe (Inhibitor of Cholesterol Absorption) 111.7 Lamotrigine (Discovery of a Standalone Drug for the Treatment of Epilepsy) 131.8 Omeprazole (Proton Pump Inhibitor Acid-Suppressive Agent) 151.9 Outlook 17Acknowledgments 17List of Abbreviations 17References 182 Drug Discoveries and Molecular Mechanism of Action 19David C. Swinney2.1 Introduction 192.2 Mechanistic Paradox 192.3 Molecular Mechanism of Action 202.4 How MMOAs were Discovered 252.5 Case Study: Artemisinin 302.6 Summary 31List of Abbreviations 32References 32Part II Drug Class 353 Insulin Analogs – Improving the Therapy of Diabetes 37John M. Beals3.1 Introduction 373.2 Pharmacology and Insulin Analogs 383.3 Chemical Description 393.4 Rapid-Acting Insulin Analogs (Prandial or Bolus Insulin) 413.5 Long-Acting Insulin Analog Formulations (Basal Insulin) 483.6 Conclusions and Future Considerations 54List of Abbreviations 55References 55Part III Case Histories 614 The Discovery of Stendra™(Avanafil) for the Treatment of Erectile Dysfunction 63Koichiro Yamada, Toshiaki Sakamoto, Kenji Omori, and Kohei Kikkawa4.1 Introduction 634.2 Discovery of Avanafil 654.4 Clinical Studies of Avanafil 814.5 Conclusion 83List of Abbreviations 83References 835 Dapagliflozin, A Selective SGLT2 Inhibitor for Treatment of Diabetes 87William N.Washburn5.1 Introduction 875.2 Role of SGLT2 Transporters in Renal Function 885.3 O-Glucoside SGLT2 Inhibitors 895.4 m-Diarylmethane C-Glucosides 975.5 Profiling Studies with Dapagliflozin 1055.6 Clinical Studies with Dapagliflozin 1085.7 Summary 108List of Abbreviations 109References 1106 Elvitegravir, A New HIV-1 Integrase Inhibitor for Antiretroviral Therapy 113Hisashi Shinkai6.1 Introduction 1136.2 Discovery of Elvitegravir 1146.3 Conclusion 121List of Abbreviations 123References 1237 Discovery of Linagliptin for the Treatment of Type 2 Diabetes Mellitus 129Matthias Eckhardt, Thomas Klein, Herbert Nar, and Sandra Thiemann7.1 Introduction 1297.2 Discovery of Linagliptin – HighThroughput Screening Hit Optimization 1307.3 Rationalization of DPP-4 Inhibition Potency by Crystal Structure Analysis and Studies of Binding Kinetics 1397.4 Basic Physicochemical, Pharmacological, and Kinetic Characteristics 1417.5 Preclinical Studies 1437.6 Clinical Studies 1467.7 Conclusion 151List of Abbreviations 151References 1528 The Discovery of Alimta (Pemetrexed) 157Edward C. TaylorList of Abbreviations 175References 1769 Perampanel: A Novel, Noncompetitive AMPA Receptor Antagonist for the Treatment of Epilepsy 181Shigeki Hibi9.1 Introduction 1819.2 Seeds Identification by High Throughput Screening (HTS) Assays 1839.3 Structure and Activity Relationship (SAR) Study Starting from the Unique Structure of Seed Compounds 1849.4 Pharmacological Properties of Perampanel; Selection for Clinical Development 1879.5 Clinical Development of Perampanel 1899.6 Conclusion 190List of Abbreviations 190References 19110 Discovery and Development of Telaprevir (Incivek™) – A Protease Inhibitor to Treat Hepatitis C Infection 195Bhisetti G. Rao, Mark A. Murcko, Mark J. Tebbe, and Ann D. Kwong10.1 Introduction 19510.2 Discussion 19710.3 Summary 207List of Abbreviations 208References 20911 Antibody–Drug Conjugates: Design and Development of Trastuzumab Emtansine (T-DM1) 213Sandhya Girish, Gail D. Lewis Phillips, Fredric S. Jacobson, Jagath R. Junutula, and Ellie Guardino11.1 Introduction 21311.2 Molecular Design of T-DM1 21411.3 Strategies for Bioanalysis 21611.4 Strategies for Chemistry and Manufacturing Control 21811.5 Nonclinical Development 21911.6 Clinical Pharmacology 22011.7 Clinical Trials and Approval 22211.8 Summary 224List of Abbreviations 225References 226Index 231

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. He is the author of some 100 patents and scientific publications. In 2004, he was elected as a Titular member of the Chemistry and Human Health Division of IUPAC. He received an honorary professorship at the Technical University of Budapest.David Rotella is the Margaret and Herman Sokol Professor of Medicinal Chemistry at Montclair State University. He earned a B.S. Pharm. degree at the University of Pittsburgh (1981) and a Ph.D. (1985) at The Ohio State University with Donald. T. Witiak. After postdoctoral studies in organic chemistry at Penn State University with Ken S. Feldman, he became an assistant professor at the University of Mississippi. Before accepting his current position he worked at Cephalon, Bristol-Myers, Lexicon and Wyeth where he was involved in neurodegeneration, schizophrenia, cardiovascular and metabolic disease drug discovery projects.

"In summary, this book provides a diverse set of insights into successful drug discovery cases and concepts. It is highly valuable both to support teaching and as a motivating read for medicinal chemists in academia and industry." (ChemMedChem, 1 October 2015)"Because of the manner in which this book combines basic broad concepts (Section I), a detailed overview of an class of molecules (Section II), and narrowly focused case studies (Section III), it would be a valuable addition to the library of any group doing drug discovery and development." (Chemistry International 2016)

• Preface XIIIList of Contributors XVIIPart I General Aspects 11 Serendipitous Target-Based Drug Discoveries 3Janos Fischer and David P. Rotella1.1 Introduction 31.2 Recent Examples of Target-Based Drug Discovery 41.3 Serendipitous Target-Based Drug Discoveries 71.4 Drospirenone (Contraceptive with Anti-aldosterone Activity) 71.5 Escitalopram (Selective Serotonin Reuptake Inhibitor Antidepressant) 91.6 Ezetimibe (Inhibitor of Cholesterol Absorption) 111.7 Lamotrigine (Discovery of a Standalone Drug for the Treatment of Epilepsy) 131.8 Omeprazole (Proton Pump Inhibitor Acid-Suppressive Agent) 151.9 Outlook 17Acknowledgments 17List of Abbreviations 17References 182 Drug Discoveries and Molecular Mechanism of Action 19David C. Swinney2.1 Introduction 192.2 Mechanistic Paradox 192.3 Molecular Mechanism of Action 202.4 How MMOAs were Discovered 252.5 Case Study: Artemisinin 302.6 Summary 31List of Abbreviations 32References 32Part II Drug Class 353 Insulin Analogs – Improving the Therapy of Diabetes 37John M. Beals3.1 Introduction 373.2 Pharmacology and Insulin Analogs 383.3 Chemical Description 393.4 Rapid-Acting Insulin Analogs (Prandial or Bolus Insulin) 413.5 Long-Acting Insulin Analog Formulations (Basal Insulin) 483.6 Conclusions and Future Considerations 54List of Abbreviations 55References 55Part III Case Histories 614 The Discovery of Stendra™(Avanafil) for the Treatment of Erectile Dysfunction 63Koichiro Yamada, Toshiaki Sakamoto, Kenji Omori, and Kohei Kikkawa4.1 Introduction 634.2 Discovery of Avanafil 654.4 Clinical Studies of Avanafil 814.5 Conclusion 83List of Abbreviations 83References 835 Dapagliflozin, A Selective SGLT2 Inhibitor for Treatment of Diabetes 87William N.Washburn5.1 Introduction 875.2 Role of SGLT2 Transporters in Renal Function 885.3 O-Glucoside SGLT2 Inhibitors 895.4 m-Diarylmethane C-Glucosides 975.5 Profiling Studies with Dapagliflozin 1055.6 Clinical Studies with Dapagliflozin 1085.7 Summary 108List of Abbreviations 109References 1106 Elvitegravir, A New HIV-1 Integrase Inhibitor for Antiretroviral Therapy 113Hisashi Shinkai6.1 Introduction 1136.2 Discovery of Elvitegravir 1146.3 Conclusion 121List of Abbreviations 123References 1237 Discovery of Linagliptin for the Treatment of Type 2 Diabetes Mellitus 129Matthias Eckhardt, Thomas Klein, Herbert Nar, and Sandra Thiemann7.1 Introduction 1297.2 Discovery of Linagliptin – HighThroughput Screening Hit Optimization 1307.3 Rationalization of DPP-4 Inhibition Potency by Crystal Structure Analysis and Studies of Binding Kinetics 1397.4 Basic Physicochemical, Pharmacological, and Kinetic Characteristics 1417.5 Preclinical Studies 1437.6 Clinical Studies 1467.7 Conclusion 151List of Abbreviations 151References 1528 The Discovery of Alimta (Pemetrexed) 157Edward C. TaylorList of Abbreviations 175References 1769 Perampanel: A Novel, Noncompetitive AMPA Receptor Antagonist for the Treatment of Epilepsy 181Shigeki Hibi9.1 Introduction 1819.2 Seeds Identification by High Throughput Screening (HTS) Assays 1839.3 Structure and Activity Relationship (SAR) Study Starting from the Unique Structure of Seed Compounds 1849.4 Pharmacological Properties of Perampanel; Selection for Clinical Development 1879.5 Clinical Development of Perampanel 1899.6 Conclusion 190List of Abbreviations 190References 19110 Discovery and Development of Telaprevir (Incivek™) – A Protease Inhibitor to Treat Hepatitis C Infection 195Bhisetti G. Rao, Mark A. Murcko, Mark J. Tebbe, and Ann D. Kwong10.1 Introduction 19510.2 Discussion 19710.3 Summary 207List of Abbreviations 208References 20911 Antibody–Drug Conjugates: Design and Development of Trastuzumab Emtansine (T-DM1) 213Sandhya Girish, Gail D. Lewis Phillips, Fredric S. Jacobson, Jagath R. Junutula, and Ellie Guardino11.1 Introduction 21311.2 Molecular Design of T-DM1 21411.3 Strategies for Bioanalysis 21611.4 Strategies for Chemistry and Manufacturing Control 21811.5 Nonclinical Development 21911.6 Clinical Pharmacology 22011.7 Clinical Trials and Approval 22211.8 Summary 224List of Abbreviations 225References 226Index 231