Case Studies in Modern Drug Discovery and Development

Xianhai Huang, PhD, is a Principal Scientist at Merck Research Laboratories. Dr. Huang is the inventor or co-inventor on more than forty patents and patent applications. As a mentor in the Schering-Plough chemistry postdoctoral program, Dr. Huang and his group discovered novel synthetic applications of (diacetoxyiodo) benzene and successfully applied the methodology to the total synthesis of psymberin, an antitumor natural product.Robert G. Aslanian, PhD, is an adjunct professor of chemistry at William Paterson University and was formerly a Senior Director of Medicinal Chemistry with the Schering-Plough Research Institute and Merck Research Laboratories. Dr. Aslanian has over twenty-five years of experience in the pharmaceutical industry. He is co-inventor on thirty-eight U.S. patents and coauthor on sixty-seven scientific articles and reviews.

• Preface xvContributors xviiChapter 1 Introduction: Drug Discovery in Difficult Times 1Malcolm MacCossChapter 2 Discovery and Development of The DPP-4 Inhibitor Januvia® (SITA-GLIPTIN) 10Emma R. Parmee, Ranabir SinhaRoy, Feng Xu, Jeffrey C. Givand, and Lawrence A. Rosen2.1 Introduction 102.2 DPP-4 Inhibition as a Therapy for Type 2 Diabetes: Identification of Key Determinants for Efficacy and Safety 102.2.1 Incretin-Based Therapy for T2DM 102.2.2 Biological Rationale: DPP-4 is a Key Regulator of Incretin Activity 112.2.3 Injectable GLP-1 Mimetics for the Treatment of T2DM 122.2.4 DPP-4 Inhibition as Oral Incretin-Based Therapy for T2DM 122.2.5 Investigation of DPP-4 Biology: Identification of Candidate Substrates 132.2.6 Preclinical Toxicities of In-Licensed DPP-4 Inhibitors 152.2.7 Correlation of Preclinical Toxicity with Off-Target Inhibition of Pro-Specific Dipeptidase Activity 162.2.8 Identification of Pro-Specific Dipeptidases Differentially Inhibited by the Probiodrug Compounds 172.2.9 A Highly Selective DPP-4 Inhibitor is Safe and Well Tolerated in Preclinical Species 192.2.10 A Highly Selective DPP-4 Inhibitor Does Not Inhibit T-Cell Proliferation in vitro 192.2.11 DPP-4 Inhibitor Selectivity as a Key Parameter for Drug Development 202.3 Medicinal Chemistry Program 202.3.1 Lead Generation Approaches 202.3.2 Cyclohexyl Glycine α-Amino Acid Series of DPP-4 Inhibitors 202.3.3 Improving Selectivity of theα-Amino Acid Series 222.3.4 Identification and Optimization of the β-Amino Acid Series 222.4 Synthetic and Manufacturing Routes to Sitagliptin 272.4.1 Medicinal Chemistry Route to Sitagliptin and Early Modifications 272.4.2 An Asymmetric Hydrogenation Manufacturing Route to Sitagliptin 282.4.3 A “Greener” Manufacturing Route to Sitagliptin Employing Biocatalytic Transamination 312.5 Drug Product Development 332.5.1 Overview 332.5.2 Composition Development 332.5.3 Manufacturing Process Development 332.6 Clinical Studies 362.6.1 Preclinical PD Studies and Early Clinical Development of Sitagliptin 362.6.2 Summary of Phase II/III Clinical Trials 382.7 Summary 39References 39Chapter 3 Olmesartan Medoxomil: An Angiotensin II Receptor Blocker 45Hiroaki Yanagisawa, Hiroyuki Koike, and Shin-ichiro Miura3.1 Background 453.1.1 Introduction 453.1.2 Prototype of Orally Active ARBs 463.2 The Discovery of Olmesartan Medoxomil (Benicar) 473.2.1 Lead Generation 473.2.2 Lead Optimization 493.3 Characteristics of Olmesartan 533.4 Binding Sites of Omlersartan to the AT1 Receptor and Its Inverse Agonoist Activity 563.4.1 Binding Sites of Olmesartan to the AT1 Receptor 563.4.2 Inverse Agonist Activity of Olmesartan 563.4.3 Molecular Model of the Interaction between Olmesartan and the AT1 Receptor 573.5 Practical Preparation of Olmesartan Medoxomil 583.6 Preclinical Studies 583.6.1 AT1 Receptor Blocking Action 583.6.2 Inhibition of Ang II-Induced Vascular Contraction 593.6.3 Inhibition of the Pressor Response to Ang II 603.6.4 Blood Pressure Lowering Effects 603.6.5 Organ Protection 613.7 Clinical Studies 623.7.1 Antihypertensive Efficacy and Safety 623.7.2 Organ Protection 633.8 Conclusion 63References 64Chapter 4 Discovery of Heterocyclic Phosphonic Acids as Novelampmimics That Are Potent and Selective Fructose-1,6-Bisphosphatase Inhibitors and Elicit Potent Glucose-Lowering Effects in Diabetic Animals and Humans 67Qun Dang and Mark D. Erion4.1 Introduction 674.2 The Discovery of MB06322 694.2.1 Research Operation Plan 694.2.2 Discovery of Nonnucleotide AMP Mimics as FBPase Inhibitors 694.2.3 Discovery of Benzimidazole Phosphonic Acids as FBPase Inhibitors 744.2.4 Discovery of Thiazole Phosphonic Acids as Potent and Selective FBPase Inhibitors 774.2.5 The Discovery of MB06322 Through Prodrug Strategy 804.3 Pharmacokinetic Studies of MB06322 824.4 Synthetic Routes to MB06322 834.5 Clinical Studies of MB06322 834.5.1 Efficacy Study of Thiazole 12.6 in Rodent Models of T2DM 834.5.2 Phase I/II Clinical Studies 844.6 Summary 84References 85Chapter 5 Setting The Paradigm of Targeted Drugs for The Treatment of Cancer: Imatinib and Nilotinib, Therapies for Chronic Myelogenous Leukemia 88Paul W. Manley and Jurg Zimmermann5.1 Introduction 885.2 Chronic Myelogenous Leukemia (CML) and Early Treatment of the Disease 895.3 Imatinib: A Treatment for Chronic Myelogenous Leukemia (CML) 925.4 The Need for New Inhibitorts of BCR-ABL1 and Development of Nilotinib 945.5 Conclusion 99References 100Chapter 6 Amrubicin, A Completely Synthetic 9-Aminoanthracycline for Extensive-Disease Small-Cell Lung Cancer 103Mitsuharu Hanada6.1 Introduction 1036.2 The Discovery of Amrubicin: The First Completely Synthetic Anthracycline 1066.3 Toxicological Profile of Amrubicin 1076.4 DNA Topoisomerase II Inhibition and Apoptosis Induction by Amrubicin 1106.5 Amrubicin Metabolism: The Discovery of Amrubicinol 1136.5.1 Amrubicinol Functions as an Active Metabolite of Amrubicin 1136.5.2 Tumor-Selective Metabolism of Amrubicin to Amrubicinol 1156.6 Improved Usage of Amrubicin 1166.7 Clinical Trials 1186.7.1 Clinical Trials of Amrubicin as First-line Therapy in Patients with ED-SCLC 1186.7.2 Clinical Trials of Amrubicin as Second-Line Therapy in Patients with ED-SCLC 1216.8 Conclusions 122References 123Chapter 7 The Discovery of Dual IGF-1R and IR Inhibitor FQIT for the Treatment of Cancer 127Meizhong Jin, Elizabeth Buck, and Mark J. Mulvihill7.1 Biological Rational for Targeting the IGF-1R/IR Pathway for Anti-Cancer Therapy 1277.2 Discovery of OSI-906 1287.2.1 Summary of OSI-906 Discovery 1287.2.2 OSI-906 Clinical Aspects 1297.3 OSI-906 Back Up Efforts 1317.4 The Discovery of FQIT 1317.4.1 Lead Generation Strategy 1317.4.2 Small Molecule Dual IGF-1R/IR Inhibitor Drug Discovery Cascade 1337.4.3 Initial Proof-of-Concept Compounds 1347.4.4 Synthesis of 5,7-Disubstituted Imidazo[5,1-f][1,2,4] Triazines 1357.4.5 Lead Imidazo[5,1-f][1,2,4] Triazine IGF-1R/IR Inhibitors and Emergence of FQIT 1397.5 In Vitro Profile of FQIT 1407.5.1 Cellular and Antiproliferative Effects as a Result of IGF-1R and IR Inhibition 1407.5.2 Cellular Potency in the Presence of Plasma Proteins 1417.5.3 In Vitro Metabolism and CYP450 Profile 1437.6 Pharmacokinetic Properties of FQIT 1447.6.1 formulation and Salt Study 1447.6.2 Pharmacokinetics Following Intravenous Administration 1447.6.3 Pharmacokinetics Following Oral Administration 1457.7 In Vivo Profile of FQIT 1467.7.1 In Vivo Pharmacodynamic and PK/PD Correlation 1467.7.2 In Vivo Efficacy 1467.8 Safety Assessment and Selectivity Profile of FQIT 1487.8.1 Effects on Blood Glucose and Insulin Levels 1487.8.2 Oral Glucose Tolerance Test 1487.8.3 Ames, Rodent, and Nonrodent Toxicology Studies 1497.8.4 Selectivity Profile of FQIT 1497.9 Summary 150Acknowledgments 151References 151Chapter 8 Discovery and Development of Montelukast (Singulair®) 154Robert N. Young8.1 Introduction 1548.2 Drug Development Strategies 1588.3 LTD4 Antagonist Program 1598.3.1 Lead Generation and Optimization 1598.3.2 In Vitro and In Vivo Assays 1598.4 The Discovery of Montelukast (Singulair®) 1608.4.1 First-Generation Antagonists (Figure 8.3) 1608.4.2 Discovery of MK-571 1638.4.3 Discovery of MK-0679 (29) 1688.4.4 Discovery of Montelukast (L-706,631, MK-0476, Singulair®) 1718.5 Synthesis of Montelukast 1748.5.1 Medicinal Chemistry Synthesis 1748.5.2 Process Chemistry Synthesis [104, 105] (Schemes 8.5 and 8.6) 1768.6 ADME Studies with MK-0476 (Montelukast) 1798.7 Safety Assessment of Montelukast 1808.8 Clinical Development of Montelukast 1808.8.1 Human Pharmacokinetics, Safety, and Tolerability 1808.8.2 Human Pharmacology 1818.8.3 Phase 2 Studies in Asthma 1828.8.4 Phase 3 Studies in Asthma 1828.8.5 Effects of Montelukast on Inflammation 1858.8.6 Montelukast and Allergic Rhinitis 1858.9 Summary 1858.9.1 Impact on Society 1858.9.2 Lessons Learned 1868.10 Personal Impact 187References 188Chapter 9 Discovery and Development of Maraviroc, A CCR5 Antagonist for the Treatment of HIV Infection 196Patrick Dorr, Blanda Stammen, and Elna van der Ryst9.1 Background and Rationale 1969.2 The Discovery of Maraviroc 1999.2.1 HTS and Biological Screening to Guide Medicinal Chemistry 1999.2.2 Hit Optimization 2009.2.3 Overcoming Binding to hERG 2019.3 Preclinical Studies 2019.3.1 Metabolism and Pharmacokinetic Characteristics of Maraviroc 2019.3.2 Maraviroc Preclinical Pharmacology 2029.3.3 Preclinical Investigations into HIV Resistance 2029.3.4 Binding of Maraviroc to CCR5 2049.4 The Synthesis of Maraviroc 2059.5 Nonclinical Safety and Toxicity Studies 2069.5.1 Safety Pharmacology 2069.5.2 Immuno- and Mechanistic Toxicity 2069.6 Clinical Development of Maraviroc 2079.6.1 Phase 1 Studies 2079.6.2 Phase 2a Studies 2099.6.3 Phase 2b/3 Studies 2109.6.4 Development of Resistance to CCR5 Antagonists In Vivo 2139.7 Summary, Future Directions, and Challenges 214Acknowledgments 217References 217Chapter 10 Discovery of Antimalarial Drug Artemisinin and Beyond 227Weiwei Mao, Yu Zhang, and Ao Zhang10.1 Introduction: Natural Products in Drug Discovery 22710.2 Natural Product Drug Discovery in China 22710.3 Discovery of Artemisinin: Background, Structural Elucidation and Pharmacological Evaluation 22810.3.1 Background and Biological Rationale 22810.3.2 The Discovery of Artemisinin through Nontraditional Drug Discovery Process 22910.3.3 Structural Determination of Artemisinin 23110.3.4 Pharmacological Evaluation and Clinical Trial Summary of Artemisinin 23110.4 The Synthesis of Artemisinin 23210.4.1 Synthesis of Artemisinin using Photooxidation of Cyclic or Acyclic Enol Ether as the Key Step 23310.4.2 Synthesis of Artemisinin by Photooxidation of Dihydroarteannuic Acid 23610.4.3 Synthesis of Artemisinin by Ozonolysis of a Vinylsilane Intermediate 23610.5 SAR Studies of Structural Derivatives of Artemisinin: The Discovery of Artemether 23810.5.1 C-10-Derived Artemisinin Analogs 24010.5.2 C-9 and C-9,10 Double Substituted Analogs 24510.5.3 C-3 Substituted Analogs 24610.5.4 C-6 or C-7 Substituted Derivatives 24610.5.5 C-11-Substituted Analogs 24710.6 Development of Artemether 24810.6.1 Profile and Synthesis of Artemether 24810.6.2 Clinical Studies Aspects of Artemether 24910.7 Conclusion and Perspective 250Acknowledgment 250References 251Chapter 11 Discovery and Process Development of MK-4965, A Potent Nonnucleoside Reverse Transcriptase Inhibitor 257Yong-Li Zhong, Thomas J. Tucker, and Jingjun Yin11.1 Introduction 25711.2 The Discovery of MK-4965 26011.2.1 Background Information 26011.2.2 SAR Studies Leading to the Discovery of MK-4965 26211.3 Preclinical and Clinical Studies of MK-4965 (19) 26611.4 Summary of Back-Up SAR Studies of MK-4965 Series 26611.5 Process Development of MK-4965 (19) 26711.5.1 Medicinal Chemistry Route 26711.5.2 Process Development 26911.6 Conclusion 29011.6.1 Lessons Learned from the Medicinal Chemistry Effort of MK-4965 Discovery 29011.6.2 Summary and Lessons Learned from the Process Development of MK-4965 291Acknowledgments 291References 291Chapter 12 Discovery of Boceprevir and Narlaprevir: The First and Second Generation of HCV NS3 Protease Inhibitors 296Kevin X. Chen and F. George Njoroge12.1 Introduction 29612.2 HCV NS3 Protease Inhibitors 29812.3 Research Operation Plan and Biological Assays 30212.3.1 Research Operation Plan 30212.3.2 Enzyme Assay 30212.3.3 Replicon Assay 30212.3.4 Measure of Selectivity 30312.4 Discovery of Boceprevir 30312.4.1 Initial Lead Generation Through Structure-Based Drug Design 30312.4.2 SAR Studies Focusing on Truncation, Depeptization, and Macrocyclisation 30412.4.3 Individual Amino Acid Residue Modifications 30712.4.4 Correlations Between P1, P3, and P3 Capping: The Identification of Boceprevir 31512.5 Profile of Boceprevir 31712.5.1 In Vitro Characterization of Boceprevir 31712.5.2 Pharmacokinetics of Boceprevir 31712.5.3 The Interaction of Boceprevir with NS3 Protease 31812.6 Clinical Development and Approval of Boceprevir 31912.7 Synthesis of Boceprevir 31912.8 Discovery of Narlaprevir 32212.8.1 Criteria for the Back-up Program of Boceprevir 32212.8.2 SAR Studies 32212.8.3 Profile of Narlaprevir 32612.8.4 Clinical Development Aspects of Narlaprevir 32712.8.5 Synthesis of Narlaprevir 32712.9 Summary 329References 330Chapter 13 The Discoveryofsamsca® (Tolvaptan): Thefirst Oral Nonpeptide Vasopressin Receptor Antagonist 336Kazumi Kondo and Yoshitaka Yamamura13.1 Background Information about the Disease 33613.2 Biological Rational 33713.3 Lead Generation Strategies: The Discovery of Mozavaptan 33813.4 Lead Optimization: From Mozavaptan to Tolvaptan 34713.5 Pharmacological Profiles of Tolvaptan 35013.5.1 Antagonistic Affinities of Tolvaptan for AVP Receptors 35013.5.2 Aquaretic Effect Following a Single Dose in Conscious Rats 35213.6 Drug Development 35313.6.1 Synthetic Route of Discovery and Commercial Synthesis [10a] 35313.6.2 Nonclinical Toxicology 35313.6.3 Clinical Studies 35513.7 Summary Focusing on Lessons Learned 356Acknowledgments 357References 357Chapter 14 Silodosin (Urief®, Rapaflo®, Thrupas®, Urorec®, Silodix®): A Selective α1A Adrenoceptor Antagonist for the Treatment of Benign Prostatic Hyperplasia 360Masaki Yoshida, Imao Mikoshiba, Katsuyoshi Akiyama, and Junzo Kudoh14.1 Background Information 36014.1.1 Benign Prostatic Hyperplasia 36014.1.2 α1-Adrenergic Receptors 36114.2 The Discovery of Silodosin 36214.2.1 Medicinal Chemistry 36214.2.2 The Synthesis of Silodosin (Discovery Route) 36314.2.3 Receptor Binding Studies 36514.3 Pharmacology of Silodosin 36914.3.1 Action Against Noradrenalin-Induced Contraction of Lower Urinary Tract Tissue 36914.3.2 Actions Against Phenylephrine-Induced Increase in Intraurethral Pressure and Blood Pressure 37114.3.3 Actions Against Intraurethral Pressure Increased by Stimulating Hypogastric Nerve and Blood Pressure in Dogs with Benign Prostatic Hyperplasia 37214.3.4 Safety Pharmacology 37314.4 Metabolism of Silodosin 37314.5 Pharmacokinetics of Silodosin 37614.5.1 Absorption 37614.5.2 Organ Distribution 37714.5.3 Excretion 37814.6 Toxicology of Silodosin 37914.7 Clinical Trials 38214.7.1 Phase I Studies 38214.7.2 Phase III Randomized, Placebo-Controlled, Double-Blind Study 38314.7.3 Long-Term Administration Study 38514.8 Summary: Key Lessons Learned 388References 389Chapter 15 Raloxifene: A Selective Estrogen Receptor Modulator (SERM) 392Jeffrey A. Dodge and Henry U. Bryant15.1 Introduction: SERMs 39215.2 The Benzothiophene Scaffold: A New Class of SERMs 39415.3 Assays for Biological Evaluation of Tissue Selectivity 39415.4 Benzothiophene Structure Activity 39515.5 The Synthesis of Raloxifene 40115.6 SERM Mechanism 40215.7 Raloxifene Pharmacology 40515.7.1 Skeletal System 40515.7.2 Reproductive System—Uterus 40715.7.3 Reproductive System—Mammary 40815.7.4 General Safety Profile and Other Pharmacological Considerations 41015.8 Summary 411References 411Appendix I Small Molecule Drug Discovery and Development Paradigm 417Appendix II Glossary 419Appendix III Abbreviations 432Index 443

“This book will enrich the collection of medicinal chemists or pharmacologists involved in active drug discovery research, as well as students with a passion for pursuing a career in drug discovery.”  (Doody’s, 22 February 2013) "A well-made glossary is available in the appendix, which defines the dozens of terms that a medicinal chemist will encounter in his/her career. . . This book demonstrates yet again the need for new, better medicines and the reasons for the high cost of drug research. An enjoyable read!.”  (ChemMedChem, 1 January 2013)