| Description |
1 online resource (482 pages) |
| Contents |
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 |
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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 |
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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 |
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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 |
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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 |
| Summary |
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 process Detailed biological rational and background information, drug design principles, SAR development, ADMET considerations, and clinical studies The full history of individual marketed small molecule drugs Coverage 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 drugs The 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 |
| Notes |
11.1.2 The Ubiquitin-Proteasome System |
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Description based on publisher supplied metadata and other sources |
| Subject |
Drug development.
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Pharmacology.
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Biochemistry.
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Life Sciences.
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SCIENCE.
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Organic.
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Chemistry.
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MEDICAL.
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| Form |
Electronic book
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| Author |
Aslanian, Robert G
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Tang, Wayne H
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| ISBN |
1119627788 |
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9781119627784 |
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1119627850 |
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9781119627852 |
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1119627818 |
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9781119627814 |
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