Contemporary Accounts in Drug Discovery and Development

ISBN-13: 9781119627715 / Angielski / Twarda / 2022 / 480 str.

Xianhai Huang; Robert G. Aslanian; Wayne Haifeng Tang

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PREFACECONTRIBUTORSCHAPTER 1 CURRENT DRUG DISCOVERY: GREAT CHALLENGES AND GREAT OPPORTUNITY (AN INTRODUCTION TO CONTEMPORARY ACCOUNTS IN DRUG DISCOVERY AND DEVELOPMENT)Jeffrey J. HaleCHAPTER 2 ADVANCED COMPUTATIONAL MODELING ACCELERATING SMALL-MOLECULE DRUG DISCOVERY: A GROWING TRACK RECORD OF SUCCESSRobert Abel2.1 Introduction2.2 Essential Techniques2.2.1 Target Validation and Feasibility Assessment2.2.2 Hit Discovery2.2.3 Hit-to-lead and Lead Optimization2.3 Illustrative Applications2.3.1 Modeling Support of Target Validation, Feasibility Assessment, and Hit Discovery for Acetyl-CoA Carboxylase (ACC)2.3.2 Optimizing Selectivity in Lead Optimization for Tyrosine Kinase 22.3.3 Discovery of Novel Allosteric Covalent Inhibitors of KRASG12C2.3.4 Supporting Hit to Lead Exploration for a Series of Phosphodiesterase 2A (PDE2A) Inhibitors2.4 Conclusion and Future OutlookReferencesCHAPTER 3 DISCOVERY AND DEVELOPMENT OF THE SOLUBLE GUANYLATE CYCLASE (sGC) STIMULATOR VERICIGUAT FOR THE TREATMENT OF CHRONIC HEART FAILUREMarkus Follmann, Corina Becker, Lothar Roessig, Peter Sandner, and Johannes-Peter Stasch3.1 Introduction3.2 sGC Stimulators as Treatment Option for Heart Failure3.2.1 Persistent High Medical Need in High-risk Patients with Chronic HF3.3 Medicinal Chemistry Program3.4 Synthesis Routes towards Vericiguat3.4.1 Medicinal Chemistry Route to Vericiguat3.4.2 Development Chemistry Route to Vericiguat3.5 Preclinical Studies3.5.1 In Vitro Effects on Recombinant sGC and sGC Overexpressing Cells3.5.2 Ex Vivo Effects on Isolated Blood Vessels and Hearts3.5.3 In Vivo Effects in a Disease Model with Cardiovascular Disease and Heart- and Kidney Failure3.6 Clinical Studies3.6.1 Safety, PD, PK and PK/PD in Healthy Volunteers3.6.2 Clinical Pharmacokinetics3.6.3 Pharmacodynamic Interactions3.7 SummaryReferencesCHAPTER 4 FINDING CURES FOR ALZHEMIER'S DISEASE: FROM GAMMA SECRETASE INHIBITORS TO GAMMA SECRETASE MODULATORS AND BETA SECRETASE INHIBITORSXianhai Huang, Robert Aslanian4.1 Introduction4.1.1 Alzheimer's Disease4.1.2 Alzheimer's Disease and Amyloid Beta Theory4.2 Gamma Secretase Inhibitors Drug Discovery and Development4.2.1 Gamma Secretase Inhibitors Rationale4.2.2 The Discovery of Gamma Secretase Inhibitors SCH 9002294.2.2.1 The Discovery of 2,6-Disubstituted Piperidine Sulfonamide Gamma Secretase Inhibitors4.2.2.2 The Discovery of Tricyclic Sulfones GSIs and a Preclinical Candidate SCH 9002294.2.3 Gamma Secretase Inhibitors Summary4.3 Gamma Secretase Modulator Drug Discovery and Development4.3.1 Gamma Secretase Modulator Rationale4.3.2 The Discovery of Oxadiazoline and Oxadiazine Gamma Secretase Modulators4.3.2.1 The Pyrazolopyridine Series of Gamma Secretase Modulators4.3.2.2 The Discovery of Oxadiazoline, Oxadiazine, and Oxadiazepine Gamma Secretase Modulators4.3.2.3 Profiles of Gamma Secretase Modulator Preclinical Candidates (PCC)4.3.3 On-going Gamma Secretase Modulators Discovery4.4 Beta Secretase Inhibitors Overview4.4.1 Beta Secretase Inhibitors Rationale4.4.2 Brief Summary of Verubecestat (MK-8931) Discovery and Clinical Development4.4.3 BACE1 Inhibitors Summary4.5 SummaryAcknowledgementReferencesCHAPTER 5 DISCOVERY OF NOVEL ANTIVIRAL AGENTS ENABLED BY STRUCTURAL BIOLOGY, COMPACT MODULES AND PHENOTYPIC SCREENINGWei Zhu, Song Yang, Hongying Yun, and Hong C. Shen5.1 Introduction5.2 Discovery and Early Development of Novel Core Protein Assembly Modulators for the Treatment of chronic HBV infection5.2.1 Introduction5.2.2 Lead Generation and Optimization5.2.3 Profile of Compound 35.2.4 Approaches to Address CYP Induction Liability5.2.5 Conclusion5.3 RG7834: The First-in-class Selective and Orally Bioavailable Small Molecule HBV Expression Inhibitor with a Novel Mode of Action5.3.1 Introduction5.3.2 The Discovery of RG78345.3.2.1 Lead Generation5.3.2.2 Lead Optimization5.3.2.3 Profile of RG78345.3.2.4 Target Identification5.3.3 Conclusion5.4 Ziresovir: the Discovery of a Highly Potent, Selective and Orally Bioavailable RSV Fusion Protein Inhibitor5.4.1 Introduction5.4.2 The Discovery of Ziresovir (RO-0529 OR ARK0529)5.4.2.1 Lead Generation5.4.2.2 Lead Optimization5.4.2.3 Profile of Ziresovir5.4.2.4 Mode of Action of Ziresovir5.4.3 Clinical Studies of Ziresovir5.5 ConclusionReferencesCHAPTER 6 DISCOVERY OF SUBTYPE SELECTIVE AGONISTS OF THE GROUP II METABOTROPIC GLUTAMATE RECEPTORSJunliang Hao6.1 Background6.1.1 The Dopamine and Glutamate Hypotheses of Schizophrenia6.1.2 The Ionotropic and Metabotropic Glutamate Receptors6.1.3 Orthosteric Agonists of the Group II mGlu Receptors6.1.4 Prodrug Approach to Improve Oral Bioavailability6.1.5 Clinical Studies of 6 in Schizophrenia (via its Prodrug 7)6.1.6 Rationale for Subtype Selective Agonists of the Group II mGlu Receptors6.2 Discovery of Subtype Selective Agonist LY2812223 of the mGlu2 Receptor6.2.1 Barriers to Achieve High Subtype Selectivity at the Orthosteric Site6.2.2 Discovery of Subtype Selective Agonists for the mGlu2 Receptor6.2.3 Additional In Vitro Characterization of 116.2.4 Preclinical Pharmacokinetic Profile of 116.2.5 Preclinical Animal Model of Psychosis6.3 Discovery of Subtype Selective Agonist LY2794193 of the mGlu3 Receptor6.3.1 Discovery of Subtype Selective Agonists for the mGlu3 Receptor6.3.2 Additional In Vitro Characterization of 196.3.3 Preclinical Pharmacokinetic Profile of 196.3.4 Preclinical Animal Model6.4 Structural Basis for Subtype Selectivity6.4.1 Crystal Structures of hmGlu2 and hmGlu3 ATDs in Complex with 3 and L-Glu6.4.2 Crystal Structures of hmGlu2 and hmGlu3 ATDs in Complex with 11 and 196.4.3 Structural Basis for the mGlu2 Subtype Selectivity of 11 and the mGlu3 Subtype Selectivity of 196.5 Divergent Synthesis of 11 and 196.6 Clinical Experience with mGlu2 Selective Agonist 11 (via Its Prodrug 12)6.6.1 Human Plasma and CSF PK Profiles of 116.6.2 Biomarker6.6.3 Safety6.7 ConclusionReferencesCHAPTER 7 DISCOVERY OF TASELISIB (GDC-0032): AN INHIBITOR OF PI3Kalpha WITH SELECTIVITY OVER PI3KTimothy P. Heffron, Laurent Salphati, and Steven T. Staben7.1 Introduction7.2 Hit to Lead Efforts7.3 Final Lead Optimization Leading to Discovery of Taselisib: ADME Optimization and Achieving Selective Inhibition of PI3K over PI3K7.4 Preclinical in vivo Pharmacology of Taselisib7.5 Prediction and Clinical Assessment of Taselisib Human Pharmacokinetics7.6 ConclusionReferencesCHAPTER 8 DRUG DISCOVERY WITH DNA-ENCODED LIBRARY TECHNOLOGY: INHIBITOR OF SOLUBLE EPOXIDE HYDROLASE TO CLINICAL CANDIDATEYun Ding, Sarah K. Scott8.1 Background of DNA-encode Library Technology8.1.1 Development of Encoding Strategies8.1.2 The Encoding Strategy at GSK8.1.3 Development of DNA-Compatible Chemistry8.1.4 Methods for in vitro Selection of DNA-encoded Libraries8.1.5 Decoding, Data Analysis and Off-DNA Hit Follow up8.2 Application of DNA-encoded Library Technology in Small Molecule Drug Discovery8.3 Discovery of sEH Inhibitors via DNA-encoded Library Technology8.3.1 DEL Libraries for sEH Screening8.3.2 sEH ELT Selection8.3.3 ELT Hit Confirmation, SAR and Hit-to-lead Optimization8.3.4 Lead Optimization, Preclinical and Clinical Development: GSK2256294 as a Clinical Asset8.3.5 Clinical trials with GSK22562948.4 SummaryReferencesCHAPTER 9 DISCOVERY OF HTL26119: FAMILY B GPCR STRUCTURE-BASED DRUG DESIGN IS NOW A REALITYAndrea Bortolato, Jonathan S. Mason9.1 Introduction9.2 G Protein-Coupled Receptor Structure Based Drug Discovery9.3 The Beginning of the Family B GPCR Structural Biology Revolution9.4 Lessons Learned from the Corticotropin-Releasing Factor Receptor Type 1 Crystal Structure9.5 Structural Understanding of Glucagon and GLP1 Receptor Activation9.6 Hyperinsulinaemic Hypoglycaemia9.7 GLP1 Receptor Negative Allosteric Modulator Lead Identification9.8 GLP1 Receptor Negative Allosteric Modulator Lead Optimization9.9 ConclusionReferencesCHAPTER 10 DISCOVERY AND POTENTIAL APPLICATION OF [11C]MK-6884: A POSITRON EMISSION TOMOGRAPHY (PET) IMAGING AGENT FOR THE STUDY OF M4 MUSCARINIC RECEPTOR POSITIVE ALLOSTERIC MODULATORS (PAMs) IN NEURODEGENERATIVE DISEASESLing Tong, Wenping Li10.1 Introduction10.1.1 Positron Emission Tomography10.1.2 Muscarinic Acetylcholine Receptor 4 (M4) Positive Allosteric Modulator10.2 Discovery of a Selective PET Tracer for M4 PAM10.2.1 Criteria for a PET Tracer10.2.2 PET Feasibility Study10.2.3 PET Specific Signal is Driven by an Increase in Binding Affinity10.2.4 The Implication of Lipophilicity and Free Fraction on in vivo BPND10.2.5 Fluorine-18 Labeling Opportunity10.3. A PET Tracer That Images M4 in Rat10.4. Characterization of [11C]10 as a PET Tracer Preclinical Candidate (PCC) for Human Use10.5 Development of [11C]MK-6884AcknowledgementReferencesCHAPTER 11 TARGETED PROTEIN DEGRADATION BY PROTEOLYSIS TARGETING CHIMERAS (PROTACs): A REVOLUTION IN SMALL MOLECULE DRUG DISCOVERYWu Du11.1 The Concept of Targeted Protein Degradation11.1.1 Introduction11.1.2 The Ubiquitin-Proteasome System11.1.3 Targeted Protein Degradation by Proteolysis Targeting Chimeras (PROTACs)11.2 The Advances of with PROTACs11.2.1 Proof of Concept and Early Peptide Based PROTACs11.2.2 Small Molecule Based PROTACs: the Discovery of VHL and CRBN E3 Ligands11.2.3 Ligands for E3 Ligase11.2.4 Mechanistic Considerations: the Ternary Complex and the Kinetics11.2.5 Androgen Receptor (AR) PROTACs: a Case Study11.2.6 Novel PROTACs: Self-assembled Click-formed PROTACs (CLIPTACs), Photo-chemically Controlled PROTACs (PHOTACs), Antibody-PROTAC Conjugates11.2.7 Examples of Small Molecule Based PROTACs11.3 Pharmacokinetics and Oral Absorption Challenge11.4 PROTACs in Clinical Development11.4.1 Androgen Receptor Targeting PROTAC ARV-11011.4.2 Estrogen Receptor Targeting PROTAC ARV-47111.5 Challenges and PerspectivesAcknowledgmentsReferencesCHAPTER 12 ENTREPRENEURIAL DRUG HUNTER: MACROCYCLIC PEPTIDE MODALITIESTomi Sawyer12.1 Introduction12.2 Macrocyclic Peptide Modalities in Retrospect12.3 Receptor and Extracellularly Targeted Macrocyclic Peptides12.4 Intracellular Protein-protein Interaction Targeted Macrocyclic Peptides12.5 Macrocyclic Peptide Advancement to Clinical Development and FDA Approval12.6 Macrocyclic Peptide Drug Discovery Paradigm and Future DirectionsAcknowledgementReferencesCHAPTER 13 APPLICATION OF PYRROLOBENZODIAZEPINE (PBD) IN ANTIBODY DRUG CONJUGATESNing Zou, Amy Han13.1 Introduction13.2 Antibody drug conjugating with PBD payloads13.2.1 SG-3199 (payload), SG-3249 (linker-payload), and SG-3199 Based ADCs13.2.1.1 ADCT-30113.2.1.2 ADCT-40113.2.1.3 ADCT-40213.2.1.4 ADCT-50213.2.1.5 ADCT-60213.2.1.6 Rovalpituzumab Tesirine (Rova-T)13.2.1.7 ADCT-60113.2.1.8 MEDI222813.2.1.9 TR1801-ADC (MT-8633)13.2.2 SGD-1882 (payload), SGD-1910 (linker-payload), and SGD-1882 Based ADCs13.2.2.1 SGN-CD33A (Vadastuximab Talirine)13.2.2.2 SGN-CD70A13.2.2.3 SGN-CD19B13.2.2.4 SGN-CD123A13.2.2.5 SGN-CD352A13.2.2.6 ABBV-17613.2.2.7 ABBV-32113.2.3 IGN Payloads-based ADCs13.2.3.1 IMGN77913.2.3.2 IMGN63213.2.3.3 TAK-16413.2.4. Other PBD-based Payload ADCS13.2.4.1 PBD-MA13.2.4.2 Pyrridinobenzodiazepines (PDDs)13.2.4.3 Isoquinolidinobenzodiazepine Dimers (IQBs)13.2.4.4 PBD-Duocarmycin Dimers13.2.4.5 PBD Dimer with Thio-oxophosphane Moiety13.3 Small Molecule Drug Conjugates with pro-PBD Payloads13.3.1 N-Substituted 1,3-Oxazolidine pro-PBD13.3.2 Oxime Ether pro-PBD13.4 Discussion13.5 ConclusionReferencesCHAPTER 14 COMBINATION THERAPY CASE STUDIES IN ANTICANCER AND ANTI-INFECTIOUS DISEASE DRUG DISCOVERY AND DEVELOPMENTXianhai Huang, David Yu-Kai Chen14.1. Introduction14.1.1. Combination Therapy in Anticancer Drug Discovery and Development14.1.2. Combination Therapy in Antibacterial Drug Discovery and Development14.2. Case Study of Olaparib (Lynparza(r)) and Bevacizumab (Avastin(r)) Combination in the Treatment of Advanced Ovarian Cancer14.2.1. Discovery and Development History of Olaparib and Bevacizumab in the Treatment of Ovarian Cancer14.2.1.1 Discovery and Development History of Olaparib in the Treatment of Ovarian Cancer14.2.1.2 Discovery and Development History of Bevacizumab in the Treatment of Ovarian Cancer14.2.2. Rational Design of Olaparib and Bevacizumab Combination14.2.3. Olaparib and Bevacizumab Combination in Clinical Studies14.2.3.1. Phase I Clinical Studies of the Olaparib and Bevacizumab Combination14.2.3.2. Phase II Clinical Studies of Olaparib and Bevacizumab Combination14.2.3.3. Phase III Clinical Studies of Olaparib and Bevacizumab Combination14.2.4. Summary of the Olaparib and Bevacuzimab Combination14.3. Case Study of Ceftazidime and Avibactam Combination (Avycaz(r)) in the Treatment of Complicated Urinary Tract Infections (cUTIs) and Intra-Abdominal Infections (cIAIs)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 (cUTIs) and Intra-Abdominal Infections (cIAIs)14.3.2. PK, Safety and Tolerability of Ceftazidime and Avibactam Combination in Phase I Human Clinical Trials14.3.3. Clinical Efficacy of the Ceftazidime and Avibactam Combination14.3.3.1. Ceftazidime and Avibactam Combination Phase II Clinical Trials14.3.3.2. Ceftazidime and Avibactam Combination Phase III Clinical Trials14.3.3.2.1 Ceftazidime and Avibactam Combination Phase III Clinical Trials in the Treatment of cUTI14.3.3.2.2 Ceftazidime and Avibactam Combination Phase III Clinical Trials in the Treatment of cIAI14.3.3.2.3 Ceftazidime and Avibactam Combination Phase III Clinical Trials in the Treatment of Nosocomial Pneumonia and Ventilator-Associated Pneumonia14.3.3.2.4 Ceftazidime and Avibactam Combination Phase III Clinical Trials in the Treatment of Pediatric Patients with cUTI and cIAI14.3.4. Summary of Ceftazidime and Avibactam Combination14.4. Combination Therapy Future PerspectivesReferencesCHAPTER 15 ACCELERATING DRUG DISCOVERY AND DEVELOPMENT: TRANSLATIONAL MEDICINE IN COMBATING THE COVID19 PANDEMICXianhai Huang, David Yu-Kai Chen, and Haifeng "Wayne" Tang15.1. Introduction to Translational Medicine15.2. From Bench to Bedside: Translating Basic Research into Desirable Clinical Outcomes for COVID-19 Treatments15.2.1. The Importance of Diagnostic Biomarkers in Speeding up Testing to Contain the Spread of the COVID-19 Virus15.2.1.1. The Polymerase Chain Reaction (PCR) Test15.2.1.2. The Antigen Test15.2.1.3. The Antibody (Serological) Test15.2.2. The Discovery and Clinical Development of Remdesivir in the Era of the COVID-19 Pandemic15.2.3. COVID-19 Virus Targeting Antibody Discovery and Development15.2.4. Accelerated Vaccine Development for COVID-19 Prevention15.3. From Bedside to Bench: Accelerating Drug Discovery and Development in Treating COVID-1915.3.1. The Need for an Inhaled Formulation of Remdesivir15.3.2. Overcoming Cytokine Storm in COVID-19 Treatment15.4. Translational Medicine SummaryReferencesAPPENDIX I MONOCLONAL ANTIBODY DRUG DISCOVERY AND DEVELOPMENT PARADIGMAPPENDIX II GLOSSARYAPPENDIX III ABBREVIATIONSINDEX

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Xianhai Huang, PhD, Executive Director and Head of Discovery Chemistry at InventisBio Co., Ltd.Robert G. Aslanian, PhD, Associate Professor of Chemistry and Chair of the Department at New Jersey City University.Wayne H. Tang, PhD, Executive Director and co-Head of Medicinal Chemistry at Schrödinger Inc.