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Informationen zum Autor VARGHESE JOHN is Director of Alzheimer's Drug Discovery at the Buck Institute for Age Research. He is a chemist with many years of pharmaceutical industry experience in discovery and development of drugs for CNS diseases with a primary focus on Alzheimer's disease (AD). Dr. John has many publications and patents to his credit. Klappentext BACE inhibitors and their use in the treatment of Alzheimer's DiseaseBACE (²-site of APP cleaving enzyme) is a critical component in Alzheimer's Disease (AD), and the development of BACE inhibitors shows great potential as a therapy for the disease. BACE: Lead Target for Orchestrated Therapy of Alzheimer's Disease covers virtually all aspects of BACE from initial identification, discovery of inhibitors, and challenges in clinical development, while providing a global understanding essential for productive and successful drug discovery.This book details the story of the discovery of BACE and its role in AD and comprehensively discusses:* The development of BACE inhibitors as therapeutics for Alzheimer's disease* The research that led to the identification of BACE* New BACE inhibitors currently being clinically tested* ADME (absorption, distribution, metabolism, excretion) and clinical trial design--topics not addressed in current field literature* Cutting-edge technology such as high-throughput screening, structure-based drug design, and QSAR in context of BACE inhibitors and Alzheimer's drug discovery* Other approaches to BACE inhibition based on interaction with the precursor protein APPBy enhancing the reader's understanding of the various aspects of the BACE drug-discovery process, this much-needed reference will serve as a key resource for all scientists involved in Alzheimer's research--and inspire new approaches to treatment of AD.Note: CD-ROM/DVD and other supplementary materials are not included as part of eBook file. Zusammenfassung This book covers virtually all aspects of the rapidly developing field of beta secretase (BACE), from the original isolation and cloning of BACE, to the discovery of various classes of BACE inhibitors, to challenges in clinical development. Inhaltsverzeichnis PREFACE ACKNOWLEDGMENTS CONTRIBUTORS CHAPTER 1 BACE, APP PROCESSING, AND SIGNAL TRANSDUCTION IN ALZHEIMER'S DISEASE Dale E. Bredesen and Edward H. Koo 1.1 Introduction 1.2 BACE Cleavage of APP as a Molecular Switching Mechanism 1.3 AD: An Imbalance in Cellular Dependence? 1.4 BACE Cleavage, Caspase Cleavage, and Neuronal Trophic Dependence 1.5 BACE Cleavage of APP, Dependence Receptors, and Alzheimer Pathology 1.6 Key Mutations Proximal of APP Processing to Aß 1.7 Final Remarks CHAPTER 2 IDENTIFICATION OF BACE AS A TARGET IN ALZHEIMER'S DISEASE Robert L. Heinrikson and Sukanto Sinha 2.1 Introduction 2.2 The Search for ß-Secretase 2.3 Validation of the BACE Target 2.4 Final Remarks CHAPTER 3 BACE BIOLOGICAL ASSAYS Alfredo G. Tomasselli and Michael J. Bienkowski 3.1 Introduction 3.2 Clinical and Physiological Hallmarks of Alzheimer's Disease (AD) 3.3 APP Processing 3.4 Aspartyl Protease Classification 3.5 BACE Structure 3.6 Mechanism, Kinetics, Inhibition, and Specificity 3.7 Assay Strategies for Inhibitor Finding and Development 3.8 Common Assays Used to Identify and Study Inhibitors 3.9 BACE Assays 3.10 Final Remarks CHAPTER 4 PEPTIDIC, PEPTIDOMIMETIC, AND HTS-DERIVED BACE INHIBITORS James P. Beck and Dustin J. Mergott 4.1 Introduction 4.2 Elan/Pharmacia (Pfizer) 4.3 Oklahoma Medical Research Foundation (OMRF)/Multiple Collaborators 4.4 Eli Lilly 4.5 Merck 4.6 GlaxoSmithKline 4.7 Schering Plough <...
