Contemporary Accounts in Drug Discovery and Development

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CONTEMPORARY ACCOUNTS IN DRUG DISCOVERY AND DEVELOPMENT A useful guide for medicinal chemists and pharmaceutical scientists Drug discovery is a lengthy and complex process that typically involves identifying an unmet medical need, determining a biological target, chemical library screening to identify a lead, chemical optimization, preclinical studies and clinical trials. This process often takes many years to complete, and relies on practitioners’ knowledge of chemistry and biology, but also—and perhaps more importantly—on experience. Improving the success rate in discovery and development through a thorough knowledge of drug discovery principles and advances in technology is critical for advancement in the field. Contemporary Accounts in Drug Discovery and Development provides drug discovery scientists with the knowledge they need to quickly gain mastery of the drug discovery process. A thorough accounting is given for each drug covered within the book, as the authors provide pharmacology, drug metabolism, biology, drug development, and clinical studies for every case, with modern drug discovery principles and technologies incorporated throughout. Contemporary Accounts in Drug Discovery and Development readers will also find Case histories used as an engaging way of learning about the drug discovery/development processDetailed biological rational and background information, drug design principles, SAR development, ADMET considerations, and clinical studiesThe full history of individual marketed small molecule drugsCoverage of drug candidates that have passed Phase I clinical trials with different modalities, such as antibody drug conjugates (ADC), proteolysis-targeting chimera (PROTAC), and peptide drugsThe application of new technologies in drug discovery such as DNA-encoded libraries (DEL), positron emission tomography (PET), and physics-based computational modeling employing free energy perturbation (FEP) Contemporary Accounts in Drug Discovery and Development is a helpful tool for medicinal chemists, organic chemists, pharmacologists, and other scientists in drug research and process development. It may be considered essential reading for graduate courses in drug discovery, medicinal chemistry, drug synthesis, pharmaceutical science, and pharmacology. It is also a useful resource for pharmaceutical industry labs, as well as for libraries. Cover Title Page Copyright Page Contents Preface List of Contributors Chapter 1 Current Drug Discovery: Great Challenges and Great Opportunity (an Introduction to Contemporary Accounts in Drug Discovery and Development) References Chapter 2 Advanced Computational Modeling Accelerating Small-Molecule Drug Discovery: A Growing Track Record of Success 2.1 Introduction 2.2 Essential Techniques 2.2.1 Target Validation and Feasibility Assessment 2.2.2 Hit Discovery 2.2.3 Hit-to-lead and Lead Optimization 2.3 Illustrative Applications 2.3.1 Modeling Support of Target Validation, Feasibility Assessment, and Hit Discovery for Acetyl-CoA Carboxylase 2.3.2 Optimizing Selectivity in Lead Optimization for Tyrosine Kinase 2 2.3.3 Discovery of Novel Allosteric Covalent Inhibitors of KRASG12C 2.3.4 Supporting Hit to Lead Exploration for a Series of Phosphodiesterase 2A Inhibitors 2.4 Conclusion and Future Outlook References Chapter 3 Discovery and Development of the Soluble Guanylate Cyclase Stimulator Vericiguat for the Treatment of Chronic Heart Failure 3.1 Introduction 3.2 Soluble Guanylate Cyclase Stimulators as Treatment Option for Heart Failure 3.2.1 Persistent High Medical Need in High-Risk Patients with Chronic HF 3.3 Medicinal Chemistry Program 3.4 Synthesis Routes toward Vericiguat 3.4.1 Medicinal Chemistry Route to Vericiguat 3.4.2 Development Chemistry Route to Vericiguat 3.5 Preclinical Studies 3.5.1 In vitro Effects on Recombinant sGC and sGC Overexpressing Cells 3.5.2 Ex vivo Effects on Isolated Blood Vessels and Hearts 3.5.3 In vivo Effects in a Disease Model with CV Disease and HF and Kidney Failure 3.6 Clinical Studies 3.6.1 Safety, PD, PK and PK/PD in Healthy Volunteers 3.6.2 Clinical Pharmacokinetics 3.6.2.1 Absorption 3.6.2.2 Effect of Food 3.6.2.3 Distribution 3.6.2.4 Metabolism 3.6.2.5 Elimination 3.6.2.6 Special Populations 3.6.2.7 Drug Interactions 3.6.2.8 In vivo Assessment of Drug Interactions 3.6.3 Pharmacodynamic Interactions 3.6.4 Vericiguat Phase 2 and Phase 3 studies in HFrEF patients 3.7 Summary References Chapter 4 Finding Cures for Alzheimer’s Disease: From -Secretase Inhibitors to -Secretase Modulators and -Secretase Inhibitors 4.1 Introduction 4.1.1 Alzheimer’s Disease 4.1.2 Alzheimer’s Disease and Amyloid Beta Theory 4.2 -Secretase Inhibitors Drug Discovery and Development 4.2.1 GSIs Rationale 4.2.2 The Discovery of GSI SCH 900229 4.2.2.1 The Discovery of 2,6-Disubstituted Piperidine Sulfonamide GSIs 4.2.2.2 The Discovery of Tricyclic Sulfone GSIs and a Preclinical Candidate SCH 900229 4.2.3 Summary of GSIs 4.3 -Secretase Modulator Drug Discovery and Development 4.3.1 GSM Rationale 4.3.2 The Discovery of Oxadiazoline and Oxadiazine GSMs 4.3.2.1 The Pyrazolopyridine Series of GSMs 4.3.2.2 The Discovery of Oxadiazoline, Oxadiazine, and Oxadiazepine GSMs 4.3.2.3 Profiles of GSM Preclinical Candidates 4.3.2.4 On-going GSM Discovery 4.4 Overview of -Secretase Inhibitors 4.4.1 Rationale of -Secretase Inhibitors 4.4.2 Brief Summary of Verubecestat (MK-8931) Discovery and Clinical Development 4.4.3 Summary of BACE1 Inhibitors 4.5 Summary Acknowledgement References Chapter 5 Discovery of Novel Antiviral Agents Enabled by Structural Biology, Compact Modules and Phenotypic Screening 5.1 Introduction 5.2 Discovery and Early Development of Novel Core Protein Assembly Modulators for the Treatment of Chronic Hepatitis B Virus Infection 5.2.1 Introduction 5.2.2 Lead Generation and Optimization 5.2.3 Profile of Compound 3 5.2.4 Approaches to Address CYP Induction Liability 5.2.5 Conclusion 5.3 RG7834: The First-in-Class Selective and Orally Bioavailable Small Molecule HBV Expression Inhibitor with a Novel Mode of Action 5.3.1 Introduction 5.3.2 The Discovery of RG7834 5.3.2.1 Lead Generation 5.3.2.2 Lead Optimization 5.3.2.3 Profile of RG7834 5.3.2.4 Target Identification 5.3.3 Conclusion 5.4 Ziresovir: The Discovery of a Highly Potent, Selective and Orally Bioavailable RSV Fusion Protein Inhibitor 5.4.1 Introduction 5.4.2 The Discovery of Ziresovir (RO-0529 OR ARK0529) 5.4.2.1 Lead Generation 5.4.2.2 Lead Optimization 5.4.2.3 Profile of Ziresovir 5.4.2.4 Mode of Action of Ziresovir 5.4.3 Clinical Studies of Ziresovir 5.5 Conclusion References Chapter 6 Discovery of Subtype Selective Agonists of the Group II Metabotropic Glutamate Receptors 6.1 Background 6.1.1 The Dopamine and Glutamate Hypotheses of Schizophrenia 6.1.2 The Ionotropic and Metabotropic Glutamate Receptors 6.1.3 Orthosteric Agonists of the Group II mGlu Receptors 6.1.4 Prodrug Approach to Improve Oral Bioavailability 6.1.5 Clinical Studies of 6 in Schizophrenia (via its Prodrug 7) 6.1.6 Rationale for Subtype Selective Agonists of the Group II mGlu Receptors 6.2 Discovery of Subtype Selective Agonist LY2812223 of the MGLU2 Receptor 6.2.1 Barriers to Achieve High Subtype Selectivity at the Orthosteric Site 6.2.2 Discovery of Subtype Selective Agonists for the mGlu2 Receptor 6.2.3 Additional in vitro Characterization of 11 6.2.4 Preclinical Pharmacokinetic Profile of 11 6.2.5 Preclinical Animal Model of Psychosis 6.3 Discovery of Subtype Selective Agonist LY2794193 OF THE MGLU3 Receptor 6.3.1 Discovery of Subtype Selective Agonists for the mGlu3 Receptor 6.3.2 Additional in vitro Characterization of 19 6.3.3 Preclinical Pharmacokinetic Profile of 19 6.3.4 Preclinical Animal Model 6.4 Structural Basis for Subtype Selectivity 6.4.1 Crystal Structures of hmGlu2 and hmGlu3 ATDs in Complex with 3 and L-Glu 6.4.2 Crystal Structures of hmGlu2 and hmGlu3 ATDs in Complex with 11 and 19 6.4.3 Structural Basis for the mGlu2 Subtype Selectivity of 11 and the mGlu3 Subtype Selectivity of 19 6.5 Divergent Synthesis of 11 and 19 6.6 Clinical Experience with MGLU2 Selective Agonist 11 (Via its Prodrug 12) 6.6.1 Human Plasma and CSF PK Profiles of 11 6.6.2 Biomarker 6.6.3 Safety 6.7 Conclusion References Chapter 7 Discovery of Taselisib (GDC-0032): An Inhibitor of PI3K with Selectivity over PI3K 7.1 Introduction 7.2 Hit to Lead Efforts 7.3 Final Lead Optimization Leading to Discovery of Taselisib: ADME Optimization and Achieving Selective Inhibition of PI3K over PI3K 7.4 Preclinical in vivo Pharmacology of Taselisib 7.5 Prediction and Clinical Assessment of Taselisib Human Pharmacokinetics 7.6 Conclusion References Chapter 8 Drug Discovery with DNA-Encoded Library Technology: Inhibitor of Soluble Epoxide Hydrolase to Clinical Candidate 8.1 Background of DNA-Encoded Library Technology 8.1.1 Development of Encoding Strategies 8.1.2 The Encoding Strategy at GSK 8.1.3 Development of DNA-Compatible Chemistry 8.1.4 Methods for in vitro Selection of DNA-Encoded Libraries 8.1.5 Decoding, Data Analysis and off-DNA Hit Follow Up 8.2 Application of DNA-Encoded Library Technology in Small Molecule Drug Discovery 8.3 Discovery of Soluble Epoxide Hydrolase Inhibitors Via DNA-Encoded Library Technology 8.3.1 DELs for sEH Screening 8.3.2 sEH ELT Selection 8.3.3 ELT Hit Confirmation, SAR and Hit-ToLead Optimization 8.3.4 Lead Optimization, Preclinical and Clinical Development: GSK2256294 as a Clinical Asset 8.3.5 Clinical Trials with GSK2256294 8.4 Summary References Chapter 9 Discovery of HTL26119: Family B GPCR Structure-Based Drug Design Is Now a Reality 9.1 Introduction 9.2 G Protein-Coupled Receptor Structure-Based Drug Discovery 9.3 The Beginning of the Family B GPCR Structural Biology Revolution 9.4 Lessons Learned from the Corticotropin-Releasing Factor Receptor Type 1 Crystal Structure 9.5 Structural Understanding of Glucagon and GLP1 Receptor Activation 9.6 Hyperinsulinemic Hypoglycemia 9.7 GLP1 Receptor Negative Allosteric Modulator Lead Identification 9.8 GLP1 Receptor Negative Allosteric Modulator Lead Optimization 9.9 Conclusion References Chapter 10 Discovery and Potential Application of [11C]MK-6884: A Positron Emission Tomography Imaging Agent for the Study of M4 Muscarinic Receptor Positive Allosteric Modulators in Neurodegenerative Diseases 10.1 Introduction 10.1.1 Positron Emission Tomography 10.1.2 Muscarinic Acetylcholine Receptor 4 Positive Allosteric Modulator 10.2 Discovery of a Selective PET Tracer for M4 PAM 10.2.1 Criteria for a PET Tracer 10.2.2 PET Feasibility Study 10.2.3 PET Specific Signal Is Driven by an Increase in Binding Affinity 10.2.4 The Implication of Lipophilicity and Free Fraction on in vivo BPND 10.2.5 Fluorine-18 Labeling Opportunity 10.3 A PET Tracer that Images M4 in Rat 10.4 Characterization of [11C]10 as a PET Tracer Preclinical Candidate for Human Use 10.5 Development of [11C]MK-6884 Acknowledgement References Chapter 11 Targeted Protein Degradation by Proteolysis Targeting Chimeras: A Revolution in Small Molecule Drug Discovery 11.1 The Concept of Targeted Protein Degradation 11.1.1 Introduction 11.1.2 The Ubiquitin-Proteasome System 11.1.3 Targeted Protein Degradation by Proteolysis Targeting Chimeras 11.2 Advances with PROTACs 11.2.1 Proof of Concept and Early Peptide Based PROTACs 11.2.2 Small Molecule Based PROTACs: The Discovery of VHL and CRBN E3 Ligands 11.2.3 Ligands for E3 Ligase 11.2.4 Mechanistic Considerations: The Ternary Complex and the Kinetics 11.2.5 AR PROTACs: A Case Study 11.2.6 Novel PROTACs: Self-Assembled Click-Formed PROTACs, Photochemically Controlled PROTACs, Antibody-PROTAC Conjugates 11.2.7 Examples of Small Molecule Based PROTACs 11.3 Pharmacokinetics and Oral Absorption Challenge 11.4 PROTACs in Clinical Development 11.4.1 Androgen Receptor Targeting PROTAC ARV-110 11.4.2 Estrogen Receptor Targeting PROTAC ARV-471 11.5 Challenges and Perspectives Acknowledgement References Chapter 12 Entrepreneurial Drug Hunter: Macrocyclic Peptide Modalities 12.1 Introduction 12.2 Macrocyclic Peptide Modalities in Retrospect 12.3 Receptor and Extracellularly Targeted Macrocyclic Peptides 12.4 Intracellular Protein–Protein Interaction Targeted Macrocyclic Peptides 12.5 Macrocyclic Peptide Advancement to Clinical Development and FDA Approval 12.6 Macrocyclic Peptide Drug Discovery Paradigm and Future Directions Acknowledgements References Chapter 13 Application of Pyrrolobenzodiazepines in Antibody Drug Conjugates 13.1 Introduction 13.2 Antibody Drug Conjugating with Pyrrolobenzodiazepine Payloads 13.2.1 SG-3199 (Payload), SG-3249 (Linker-Payload), and SG-3199-Based ADCs 13.2.1.1 ADCT-301 13.2.1.2 ADCT-401 13.2.1.3 ADCT-402 13.2.1.4 ADCT-502 13.2.1.5 ADCT-602 13.2.1.6 Rovalpituzumab Tesirine (Rova-T) 13.2.1.7 ADCT-601 13.2.1.8 MEDI2228 13.2.1.9 TR1801-ADC(MT-8633) 13.2.2 SGD-1882 (Payload), SGD-1910 (Linker-Payload), and SGD-1882-Based ADCs 13.2.2.1 SGN-CD33A (Vadastuximab Talirine) 13.2.2.2 SGN-CD70A 13.2.2.3 SGN-CD19B 13.2.2.4 SGN-CD123A 13.2.2.5 SGN-CD352A 13.2.2.6 ABBV-176 13.2.2.7 ABBV-321 13.2.3 IGN Payload-Based ADCs 13.2.3.1 IMGN779 13.2.3.2 IMGN632 13.2.3.3 TAK-164 13.2.4 Other PBD-Based Payload ADCs 13.2.4.1 PBD-MA 13.2.4.2 Pyrridinobenzodiazepines 13.2.4.3 Isoquinolidinobenzodiazepine Dimers 13.2.4.4 PBD-Duocarmycin Dimers 13.2.4.5 PBD Dimer with Thio-Oxophosphane Moiety 13.3 Small Molecule Drug Conjugates with Pro-Pyrrolobenzodiazepine Payloads 13.3.1 N-Substituted 1,3-Oxazolidine pro-PBD 13.3.2 Oxime Ether pro-PBD 13.4 Discussion 13.5 Conclusion References Chapter 14 Combination Therapy Case Studies in Anticancer and Anti-Infectious Disease Drug Discovery and Development 14.1 Introduction 14.1.1 Combination Therapy in Anticancer Drug Discovery and Development 14.1.2 Combination Therapy in Antibacterial Drug Discovery and Development 14.2 Case Study of Olaparib (Lynparza®) and Bevacizumab (Avastin®) Combination in the Treatment of Advanced Ovarian Cancer 14.2.1 Discovery and Development History of Olaparib and Bevacizumab in the Treatment of Ovarian Cancer 14.2.1.1 Discovery and Development History of Olaparib in the Treatment of Ovarian Cancer 14.2.1.2 Discovery and Development History of Bevacizumab in the Treatment of Ovarian Cancer 14.2.2 Rational Design of Olaparib and Bevacizumab Combination 14.2.3 Olaparib and Bevacizumab Combination in Clinical Studies 14.2.3.1 Phase 1 Clinical Studies of the Olaparib and Bevacizumab Combination 14.2.3.2 Phase 2 Clinical Studies of the Olaparib and Bevacizumab Combination 14.2.3.3 Phase 3 Clinical Studies of the Olaparib and Bevacizumab Combination 14.2.4 Summary of the Olaparib and Bevacuzimab Combination 14.3 Case Study of Ceftazidime and Avibactam Combination (Avycaz®) in the Treatment of Complicated Urinary Tract Infections and Intra-abdominal Infections 14.3.1 Brief History of the Discovery of Ceftazidime and Avibactam and the Rational for the Combination of Ceftazidime and Avibactam in the Treatment of Complicated Urinary Tract Infections and Intra-abdominal Infections 14.3.2 PK, Safety and Tolerability of the Ceftazidime and Avibactam Combination in Phase 1 Human Clinical Trials 14.3.3 Clinical Efficacy of the Ceftazidime and Avibactam Combination 14.3.3.1 Ceftazidime and Avibactam Combination Phase 2 Clinical Trials 14.3.3.2 Ceftazidime and Avibactam Combination Phase 3 Clinical Trials 14.3.4 Summary of Ceftazidime and Avibactam Combination 14.4 Combination Therapy Future Perspectives References Chapter 15 Accelerating Drug Discovery and Development: Translational Medicine in Combating the COVID-19 Pandemic 15.1 Introduction to Translational Medicine 15.2 From Bench to Bedside: Translating Basic Research into Desirable Clinical Outcomes for COVID-19 Treatments 15.2.1 The Importance of Diagnostic Biomarkers in Speeding Up Testing to Contain the Spread of the COVID-19 Virus 15.2.1.1 The PCR Test 15.2.1.2 The Antigen Test 15.2.1.3 The Antibody (Serological) Test 15.2.2 The Discovery and Clinical Development of Remdesivir in the Era of the COVID-19 Pandemic 15.2.3 COVID-19 Virus Targeting Antibody Discovery and Development 15.2.4 Accelerated Vaccine Development for COVID-19 Prevention 15.3 From Bedside to Bench: Accelerating Drug Discovery and Development in Treating COVID-19 15.3.1 The Need for an Inhaled Formulation of Remdesivir 15.3.2 Overcoming Cytokine Storm in COVID-19 Treatment 15.4 Translational Medicine Summary References Appendix A Monoclonal Antibody Drug Discovery and Development Paradigm Appendix B Glossary Appendix C Abbreviations Index EULA