Contemporary Accounts in Drug Discovery and Development

1 Cover

2 Title Page Contemporary Accounts in Drug Discovery and Development Edited by Xianhai Huang InventisBio Co., Ltd., Florham Park, USA Robert G. Aslanian New Jersey City University, Jersey City, USA Wayne H. Tang Schrödinger Inc., New York, USA

3 Copyright Page

4 Preface

5 List of Contributors

6 1 Current Drug Discovery: Great Challenges and Great Opportunity (an Introduction to Contemporary Accounts in Drug Discovery and Development ) References

7 2 Advanced Computational Modeling Accelerating Small‐Molecule Drug Discovery: A Growing Track Record of Success 2.1 Introduction 2.2 Essential Techniques 2.3 Illustrative Applications 2.4 Conclusion and Future Outlook References

8 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 3.3 Medicinal Chemistry Program 3.4 Synthesis Routes toward Vericiguat 3.5 Preclinical Studies 3.6 Clinical Studies 3.7 Summary References

9 4 Finding Cures for Alzheimer's Disease: From γ‐Secretase Inhibitors to γ‐Secretase Modulators and β‐Secretase Inhibitors 4.1 Introduction 4.2 γ‐Secretase Inhibitors Drug Discovery and Development 4.3 γ‐Secretase Modulator Drug Discovery and Development 4.4 Overview of β‐Secretase Inhibitors 4.5 Summary Acknowledgement References

10 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 5.3 RG7834: The First‐in‐Class Selective and Orally Bioavailable Small Molecule HBV Expression Inhibitor with a Novel Mode of Action 5.4 Ziresovir: The Discovery of a Highly Potent, Selective and Orally Bioavailable RSV Fusion Protein Inhibitor 5.5 Conclusion References

11 6 Discovery of Subtype Selective Agonists of the Group II Metabotropic Glutamate Receptors 6.1 Background 6.2 Discovery of Subtype Selective Agonist LY2812223 of the MGLU 2Receptor 6.3 Discovery of Subtype Selective Agonist LY2794193 OF THE MGLU 3Receptor 6.4 Structural Basis for Subtype Selectivity 6.5 Divergent Synthesis of 11 and 19 6.6 Clinical Experience with MGLU 2Selective Agonist 11 (Via its Prodrug 12) 6.7 Conclusion References

12 7 Discovery of Taselisib (GDC‐0032): An Inhibitor of PI3Kα with Selectivity over PI3Kβ 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 PI3Kα over PI3Kβ 7.4 Preclinical in vivo Pharmacology of Taselisib 7.5 Prediction and Clinical Assessment of Taselisib Human Pharmacokinetics 7.6 Conclusion References

13 8 Drug Discovery with DNA‐Encoded Library Technology 8.1 Background of DNA‐Encoded Library Technology 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 8.4 Summary References

14 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

15 10 Discovery and Potential Application of [ 11C]MK‐6884 10.1 Introduction 10.2 Discovery of a Selective PET Tracer for M4 PAM 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

16 11 Targeted Protein Degradation by Proteolysis Targeting Chimeras: A Revolution in Small Molecule Drug Discovery 11.1 The Concept of Targeted Protein Degradation 11.2 Advances with PROTACs 11.3 Pharmacokinetics and Oral Absorption Challenge 11.4 PROTACs in Clinical Development 11.5 Challenges and Perspectives Acknowledgement References

17 12 Entrepreneurial Drug Hunter 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

18 13 Application of Pyrrolobenzodiazepines in Antibody Drug Conjugates 13.1 Introduction 13.2 Antibody Drug Conjugating with Pyrrolobenzodiazepine Payloads 13.3 Small Molecule Drug Conjugates with Pro‐Pyrrolobenzodiazepine Payloads 13.4 Discussion 13.5 Conclusion References

19 14 Combination Therapy Case Studies in Anticancer and Anti‐Infectious Disease Drug Discovery and Development 14.1 Introduction 14.2 Case Study of Olaparib (Lynparza ®) and Bevacizumab (Avastin ®) Combination in the Treatment of Advanced Ovarian Cancer 14.3 Case Study of Ceftazidime and Avibactam Combination (Avycaz ®) in the Treatment of Complicated Urinary Tract Infections and Intra‐abdominal Infections 14.4 Combination Therapy Future Perspectives References

20 15 Accelerating Drug Discovery and Development 15.1 Introduction to Translational Medicine 15.2 From Bench to Bedside: Translating Basic Research into Desirable Clinical Outcomes for COVID‐19 Treatments 15.3 From Bedside to Bench: Accelerating Drug Discovery and Development in Treating COVID‐19 15.4 Translational Medicine Summary References

21 Appendix A: Appendix AMonoclonal Antibody Drug Discovery and Development Paradigm

22 Appendix B: Appendix BGlossary

23 Appendix C: Appendix CAbbreviations

24 Index

25 End User License Agreement

1 Chapter 3 Table 3.1 Hemodynamic changes and QoL at 16 weeks in patients with high vs ... Table 3.2 Properties of the N‐substituted methyl carbamates 1, 3– 9. Table 3.3 Properties of the N‐H alkyl carbamates 10– 15. Table 3.4 Properties of the core variation compounds 16– 20, 2. Table 3.5 In vivo pharmacokinetic properties of 17, 20, vericiguat 2in com... Table 3.6 Nonclinical pharmacodynamics of vericiguat in vitro , ex vivo and Table 3.7 Population pharmacokinetic model based steady‐state geometric mea...

2 Chapter 4 Table 4.1 Profiles of compounds 14a, 14b, 15a, and 15b. Table 4.2 PK profile of SCH 900229. Table 4.3 In vitro profiles of 27and 32in comparison with 18(E‐2012). Table 4.4 PK parameters of compounds 27and 32in rat, dog, and monkey a. Table 4.5 In vivo PK/PD profile of 27and 32in rat.

3 Chapter 5Table 5.1 Discovery of C6 morpholine carboxylic acid 4‐H HAP analogues.Table 5.2 Physicochemical and ADME properties of compound 3.Table 5.3 Selected pharmacokinetics parameters of compound 3in male ICR mi...Table 5.4 Effects on HBsAg reduction of analogues 19– 35.Table 5.5 Further SAR at the C9 and C10 positions: effects on HBsAg reducti...Table 5.6 Further SAR at the C6 position: effects on HBsAg reduction and ph...Table 5.7 Rat SDPK profiles of selected BAQ compounds a.Table 5.8 Effect of Ziresovir on the wild type and mutant strains a.