Table Of ContentContemporary Accounts in Drug Discovery
and Development
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
This edition first published 2022
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Library of Congress Cataloging- in- Publication Data
Names: Huang, Xianhai, editor. | Aslanian, Robert G., editor. | Tang, Wayne
H. (Wayne Haifeng), editor.
Title: Contemporary accounts in drug discovery and development / edited by
Xianhai Huang, Robert G. Aslanian, Wayne H. Tang.
Other titles: Case studies in modern drug discovery and development.
Description: Second edition. | Hoboken, NJ : Wiley, 2022. | Preceded by
Case studies in modern drug discovery and development / edited by
Xianhai Huang, Robert G. Aslanian. 2012. | Includes bibliographical
references and index.
Identifiers: LCCN 2021055890 (print) | LCCN 2021055891 (ebook) | ISBN
9781119627715 (cloth) | ISBN 9781119627852 (adobe pdf) | ISBN
9781119627814 (epub) | ISBN 9781119627784 (oBook)
Subjects: MESH: Drug Discovery | Drug Development
Classification: LCC RM301.25 (print) | LCC RM301.25 (ebook) | NLM QV 745
| DDC 615.1/9–dc23/eng/20211228
LC record available at https://lccn.loc.gov/2021055890
LC ebook record available at https://lccn.loc.gov/2021055891
Cover Design: Wiley
Cover Image: © Sergey Nivens/Shutterstock
Set in 9.5/12.5pt STIXTwoText by Straive, Pondicherry, India
10 9 8 7 6 5 4 3 2 1
v
Contents
Preface xiii
List of Contributors xvii
1 Current Drug Discovery: Great Challenges and Great Opportunity (an Introduction to
Contemporary Accounts in Drug Discovery and Development) 1
Jeffrey J. Hale
2 Advanced Computational Modeling Accelerating Small- Molecule Drug Discovery:
A Growing Track Record of Success 9
Robert Abel
2.1 Introduction 9
2.2 Essential Techniques 10
2.2.1 Target Validation and Feasibility Assessment 10
2.2.2 Hit Discovery 11
2.2.3 Hit- to- lead and Lead Optimization 12
2.3 Illustrative Applications 13
2.3.1 Modeling Support of Target Validation, Feasibility Assessment, and Hit Discovery
for Acetyl- CoA Carboxylase 13
2.3.2 Optimizing Selectivity in Lead Optimization for Tyrosine Kinase 2 15
2.3.3 Discovery of Novel Allosteric Covalent Inhibitors of KRASG12C 16
2.3.4 Supporting Hit to Lead Exploration for a Series of Phosphodiesterase 2A Inhibitors 17
2.4 Conclusion and Future Outlook 18
3 Discovery and Development of the Soluble Guanylate Cyclase Stimulator Vericiguat
for the Treatment of Chronic Heart Failure 27
Markus Follmann, Corina Becker, Lothar Roessig, Peter Sandner, and Johannes-P eter Stasch
3.1 Introduction 27
3.2 Soluble Guanylate Cyclase Stimulators as Treatment Option for Heart Failure 28
3.2.1 Persistent High Medical Need in High-R isk Patients with Chronic HF 29
3.3 Medicinal Chemistry Program 32
3.4 Synthesis Routes toward Vericiguat 36
3.4.1 Medicinal Chemistry Route to Vericiguat 36
3.4.2 Development Chemistry Route to Vericiguat 37
3.5 Preclinical Studies 39
3.5.1 In vitro Effects on Recombinant sGC and sGC Overexpressing Cells 39
3.5.2 Ex vivo Effects on Isolated Blood Vessels and Hearts 40
vi Contents
3.5.3 In vivo Effects in a Disease Model with CV Disease and HF and Kidney Failure 40
3.6 Clinical Studies 42
3.6.1 Safety, PD, PK and PK/PD in Healthy Volunteers 42
3.6.2 Clinical Pharmacokinetics 44
3.6.2.1 Absorption 44
3.6.2.2 Effect of Food 44
3.6.2.3 Distribution 44
3.6.2.4 Metabolism 44
3.6.2.5 Elimination 44
3.6.2.6 Special Populations 45
3.6.2.7 Drug Interactions 45
3.6.2.8 In vivo Assessment of Drug Interactions 46
3.6.3 Pharmacodynamic Interactions 47
3.6.4 Vericiguat Phase 2 and Phase 3 studies in HFrEF patients 47
3.7 Summary 49
4 Finding Cures for Alzheimer’s Disease: From γ- Secretase Inhibitors to γ- Secretase
Modulators and β- Secretase Inhibitors 51
Xianhai Huang and Robert Aslanian
4.1 Introduction 51
4.1.1 Alzheimer’s Disease 51
4.1.2 Alzheimer’s Disease and Amyloid Beta Theory 52
4.2 γ- Secretase Inhibitors Drug Discovery and Development 54
4.2.1 GSIs Rationale 54
4.2.2 The Discovery of GSI SCH 900229 55
4.2.2.1 The Discovery of 2,6- Disubstituted Piperidine Sulfonamide GSIs 55
4.2.2.2 The Discovery of Tricyclic Sulfone GSIs and a Preclinical Candidate SCH 900229 57
4.2.3 Summary of GSIs 61
4.3 γ- Secretase Modulator Drug Discovery and Development 62
4.3.1 GSM Rationale 62
4.3.2 The Discovery of Oxadiazoline and Oxadiazine GSMs 64
4.3.2.1 The Pyrazolopyridine Series of GSMs 64
4.3.2.2 The Discovery of Oxadiazoline, Oxadiazine, and Oxadiazepine GSMs 66
4.3.2.3 Profiles of GSM Preclinical Candidates 67
4.3.2.4 On- going GSM Discovery 71
4.4 Overview of β- Secretase Inhibitors 71
4.4.1 Rationale of β- Secretase Inhibitors 71
4.4.2 Brief Summary of Verubecestat (MK- 8931) Discovery and Clinical Development 73
4.4.3 Summary of BACE1 Inhibitors 74
4.5 Summary 74
5 Discovery of Novel Antiviral Agents Enabled by Structural Biology, Compact Modules
and Phenotypic Screening 85
Wei Zhu, Song Yang, Hongying Yun, and Hong C. Shen
5.1 Introduction 85
5.2 Discovery and Early Development of Novel Core Protein Assembly Modulators for the
Treatment of Chronic Hepatitis B Virus Infection 85
Contents vii
5.2.1 Introduction 85
5.2.2 Lead Generation and Optimization 86
5.2.3 Profile of Compound 3 91
5.2.4 Approaches to Address CYP Induction Liability 94
5.2.5 Conclusion 96
5.3 RG7834: The First- in- Class Selective and Orally Bioavailable Small Molecule HBV
Expression Inhibitor with a Novel Mode of Action 96
5.3.1 Introduction 96
5.3.2 The Discovery of RG7834 97
5.3.2.1 Lead Generation 97
5.3.2.2 Lead Optimization 99
5.3.2.3 Profile of RG7834 101
5.3.2.4 Target Identification 102
5.3.3 Conclusion 102
5.4 Ziresovir: The Discovery of a Highly Potent, Selective and Orally Bioavailable RSV
Fusion Protein Inhibitor 104
5.4.1 Introduction 104
5.4.2 The Discovery of Ziresovir (RO- 0529 OR ARK0529) 104
5.4.2.1 Lead Generation 104
5.4.2.2 Lead Optimization 105
5.4.2.3 Profile of Ziresovir 106
5.4.2.4 Mode of Action of Ziresovir 107
5.4.3 Clinical Studies of Ziresovir 107
5.5 Conclusion 108
6 Discovery of Subtype Selective Agonists of the Group II Metabotropic
Glutamate Receptors 113
Junliang Hao
6.1 Background 113
6.1.1 The Dopamine and Glutamate Hypotheses of Schizophrenia 113
6.1.2 The Ionotropic and Metabotropic Glutamate Receptors 114
6.1.3 Orthosteric Agonists of the Group II mGlu Receptors 115
6.1.4 Prodrug Approach to Improve Oral Bioavailability 116
6.1.5 Clinical Studies of 6 in Schizophrenia (via its Prodrug 7) 116
6.1.6 Rationale for Subtype Selective Agonists of the Group II mGlu Receptors 118
6.2 Discovery of Subtype Selective Agonist LY2812223 of the MGLU Receptor 119
2
6.2.1 Barriers to Achieve High Subtype Selectivity at the Orthosteric Site 119
6.2.2 Discovery of Subtype Selective Agonists for the mGlu Receptor 120
2
6.2.3 Additional in vitro Characterization of 11 120
6.2.4 Preclinical Pharmacokinetic Profile of 11 122
6.2.5 Preclinical Animal Model of Psychosis 123
6.3 Discovery of Subtype Selective Agonist LY2794193 OF THE MGLU Receptor 124
3
6.3.1 Discovery of Subtype Selective Agonists for the mGlu Receptor 124
3
6.3.2 Additional in vitro Characterization of 19 125
6.3.3 Preclinical Pharmacokinetic Profile of 19 126
6.3.4 Preclinical Animal Model 127
6.4 Structural Basis for Subtype Selectivity 127
viii Contents
6.4.1 Crystal Structures of hmGlu and hmGlu ATDs in Complex with 3 and L- Glu 127
2 3
6.4.2 Crystal Structures of hmGlu and hmGlu ATDs in Complex with 11 and 19 128
2 3
6.4.3 Structural Basis for the mGlu Subtype Selectivity of 11 and
2
the mGlu Subtype Selectivity of 19 131
3
6.5 Divergent Synthesis of 11 and 19 132
6.6 Clinical Experience with MGLU Selective Agonist 11 (Via its Prodrug 12) 134
2
6.6.1 Human Plasma and CSF PK Profiles of 11 134
6.6.2 Biomarker 135
6.6.3 Safety 137
6.7 Conclusion 137
7 Discovery of Taselisib (GDC-0 032): An Inhibitor of PI3Kα with Selectivity over PI3Kβ 145
Timothy P. Heffron, Laurent Salphati, and Steven T. Staben
7.1 Introduction 145
7.2 Hit to Lead Efforts 146
7.3 Final Lead Optimization Leading to Discovery of Taselisib: ADME Optimization and
Achieving Selective Inhibition of PI3Kα over PI3Kβ 148
7.4 Preclinical in vivo Pharmacology of Taselisib 151
7.5 Prediction and Clinical Assessment of Taselisib Human Pharmacokinetics 152
7.6 Conclusion 154
8 Drug Discovery with DNA- Encoded Library Technology: Inhibitor of
Soluble Epoxide Hydrolase to Clinical Candidate 157
Yun Ding and Sarah K. Scott
8.1 Background of DNA- Encoded Library Technology 157
8.1.1 Development of Encoding Strategies 157
8.1.2 The Encoding Strategy at GSK 158
8.1.3 Development of DNA- Compatible Chemistry 161
8.1.4 Methods for in vitro Selection of DNA- Encoded Libraries 161
8.1.5 Decoding, Data Analysis and off-D NA Hit Follow Up 163
8.2 Application of DNA- Encoded Library Technology in Small Molecule
Drug Discovery 164
8.3 Discovery of Soluble Epoxide Hydrolase Inhibitors Via DNA- Encoded Library
Technology 165
8.3.1 DELs for sEH Screening 166
8.3.2 sEH ELT Selection 166
8.3.3 ELT Hit Confirmation, SAR and Hit- To-Lead Optimization 168
8.3.4 Lead Optimization, Preclinical and Clinical Development:
GSK2256294 as a Clinical Asset 172
8.3.5 Clinical Trials with GSK2256294 172
8.4 Summary 173
9 Discovery of HTL26119: Family B GPCR Structure- Based Drug Design Is Now
a Reality 179
Andrea Bortolato and Jonathan S. Mason
9.1 Introduction 179
9.2 G Protein- Coupled Receptor Structure- Based Drug Discovery 179
9.3 The Beginning of the Family B GPCR Structural Biology Revolution 183
