Buch, Englisch, 480 Seiten, Format (B × H): 185 mm x 261 mm, Gewicht: 1012 g
ISBN: 978-1-119-62771-5
Verlag: Wiley
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.
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PREFACE
CONTRIBUTORS
CHAPTER 1 CURRENT DRUG DISCOVERY: GREAT CHALLENGES AND GREAT OPPORTUNITY (AN INTRODUCTION TO CONTEMPORARY ACCOUNTS IN DRUG DISCOVERY AND DEVELOPMENT)
Jeffrey J. Hale
CHAPTER 2 ADVANCED COMPUTATIONAL MODELING ACCELERATING SMALL-MOLECULE DRUG DISCOVERY: A GROWING TRACK RECORD OF SUCCESS
Robert Abel
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 (ACC)
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 (PDE2A) Inhibitors
2.4 Conclusion and Future Outlook
References
CHAPTER 3 DISCOVERY AND DEVELOPMENT OF THE SOLUBLE GUANYLATE CYCLASE (sGC) STIMULATOR VERICIGUAT FOR THE TREATMENT OF CHRONIC HEART FAILURE
Markus Follmann, Corina Becker, Lothar Roessig, Peter Sandner, and Johannes-Peter Stasch
3.1 Introduction
3.2 sGC 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 towards 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 Cardiovascular Disease and Heart- and Kidney Failure
3.6 Clinical Studies
3.6.1 Safety, PD, PK and PK/PD in Healthy Volunteers
3.6.2 Clinical Pharmacokinetics
3.6.3 Pharmacodynamic Interactions
3.7 Summary
References
CHAPTER 4 FINDING CURES FOR ALZHEMIER’S DISEASE: FROM GAMMA SECRETASE INHIBITORS TO GAMMA SECRETASE MODULATORS AND BETA SECRETASE INHIBITORS
Xianhai Huang, Robert Aslanian
4.1 Introduction
4.1.1 Alzheimer’s Disease
4.1.2 Alzheimer’s Disease and Amyloid Beta Theory
4.2 Gamma Secretase Inhibitors Drug Discovery and Development
4.2.1 Gamma Secretase Inhibitors Rationale
4.2.2 The Discovery of Gamma Secretase Inhibitors SCH 900229
4.2.2.1 The Discovery of 2,6-Disubstituted Piperidine Sulfonamide Gamma Secretase Inhibitors
4.2.2.2 The Discovery of Tricyclic Sulfones GSIs and a Preclinical Candidate SCH 900229
4.2.3 Gamma Secretase Inhibitors Summary
4.3 Gamma Secretase Modulator Drug Discovery and Development
4.3.1 Gamma Secretase Modulator Rationale
4.3.2 The Discovery of Oxadiazoline and Oxadiazine Gamma Secretase Modulators
4.3.2.1 The Pyrazolopyridine Series of Gamma Secretase Modulators
4.3.2.2 The Discovery of Oxadiazoline, Oxadiazine, and Oxadiazepine Gamma Secretase Modulators
4.3.2.3 Profiles of Gamma Secretase Modulator Preclinical Candidates (PCC)
4.3.3 On-going Gamma Secretase Modulators Discovery
4.4 Beta Secretase Inhibitors Overview
4.4.1 Beta Secretase Inhibitors Rationale
4.4.2 Brief Summary of Verubecestat (MK-8931) Discovery and Clinical Development
4.4.3 BACE1 Inhibitors Summary
4.5 Summary
Acknowledgement
References
CHAPTER 5 DISCOVERY OF NOVEL ANTIVIRAL AGENTS ENABLED BY STRUCTURAL BIOLOGY, COMPACT MODULES AND PHENOTYPIC SCREENING
Wei Zhu, Song Yang, Hongying Yun, and Hong C. Shen
5.1 Introduction
5.2 Discovery and Early Development of Novel Core Protein Assembly Modulators for the Treatment of chronic HBV 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
Junliang Hao
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
