05532nam 2200685Ia 450 991081007540332120200520144314.01-282-49175-X97866124917570-470-59408-X0-470-59407-1(CKB)2670000000011619(EBL)496021(OCoLC)609858657(SSID)ssj0000356923(PQKBManifestationID)11248141(PQKBTitleCode)TC0000356923(PQKBWorkID)10350889(PQKB)10782761(MiAaPQ)EBC496021(Au-PeEL)EBL496021(CaPaEBR)ebr10373024(CaONFJC)MIL249175(PPN)151784418(EXLCZ)99267000000001161920090904d2010 uy 0engurcn|||||||||txtccrBACE lead target for orchestrated therapy of Alzheimer's disease /edited by Varghese John1st ed.Hoboken, NJ John Wiley & Sonsc20101 online resource (284 p.)Description based upon print version of record.0-470-29342-X Includes bibliographical references and index.BACE; CONTENTS; PREFACE; ACKNOWLEDGMENTS; CONTRIBUTORS; CHAPTER 1 BACE, APP PROCESSING, AND SIGNAL TRANSDUCTION IN ALZHEIMER'S DISEASE; 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 Aβ; 1.7 Final Remarks; CHAPTER 2 IDENTIFICATION OF BACE AS A TARGET IN ALZHEIMER'S DISEASE; 2.1 Introduction; 2.2 The Search for β-Secretase2.3 Validation of the BACE Target 2.4 Final Remarks; CHAPTER 3 BACE BIOLOGICAL ASSAYS; 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; 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; 4.8 Bristol-Myers Squibb; 4.9 Novartis; 4.10 Amgen; 4.11 Wyeth; 4.12 Final Remarks; CHAPTER 5 FRAGMENT-BASED APPROACHES FOR IDENTIFICATION OF BACE INHIBITORS; 5.1 Introduction; 5.2 Biophysical Methods Applied to BACE Fragment Screens; 5.3 BACE Inhibitors Identified by Fragment Screening; 5.4 Final Remarks; CHAPTER 6 STRUCTURE-BASED DESIGN OF BACE INHIBITORS: TECHNICAL AND PRACTICAL ASPECTS OF PREPARATION, 3-DIMENSIONAL STRUCTURE, AND COMPUTATIONAL ANALYSIS6.1 Introduction 6.2 Preparation of BACE for Structural Studies; 6.3 Crystallographic Studies of BACE; 6.4 Structural Studies with BACE Inhibitors: Peptidomimetics and Nonpeptidomimetics; 6.5 Computational Approaches; 6.6 Final Remarks; CHAPTER 7 PHARMACOLOGICAL MODELS FOR PRECLINICAL TESTING: FROM MOUSE TO DOG TO NONHUMAN PRIMATES; 7.1 Introduction; 7.2 BACE 1 and Mouse Models of AD; 7.3 Testing BACE Inhibitors in the Canine Model of Human Aging and AD; 7.4 BACE Inhibitors and Nonhuman Primates; 7.5 Final RemarksCHAPTER 8 ADSORPTION, DISTRIBUTION, METABOLISM, EXCRETION (ADME), EFFICACY, AND TOXICOLOGY FOR BACE INHIBITORS 8.1 Introduction; 8.2 Development of BACE Inhibitors with Optimized ADME Properties; 8.3 In Vivo Efficacy of BACE Inhibitors; 8.4 Toxicology of BACE Inhibitors; 8.5 Final Remarks; CHAPTER 9 CLINICAL TRIALS FOR DISEASE-MODIFYING DRUGS SUCH AS BACE INHIBITORS; 9.1 Introduction; 9.2 Update on Beta-Amyloid Therapies in Clinical Development; 9.3 Clinical Development of BACE Inhibitors and Other Disease-Modifying Drugs; 9.4 Final RemarksCHAPTER 10 FUTURE STRATEGIES FOR DEVELOPMENT OF NOVEL BACE INHIBITORS: ANTI-APP β-SITE ANTIBODY AND APP BINDING SMALL MOLECULE APPROACHES FOR ALZHEIMER'S DISEASEBACE inhibitors and their use in the treatment of Alzheimer's Disease BACE (ß-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 discAlzheimer's diseaseChemotherapyAspartic proteinasesInhibitorsTherapeutic useAmyloid beta-protein precursorAlzheimer's diseaseChemotherapy.Aspartic proteinasesInhibitorsTherapeutic use.Amyloid beta-protein precursor.618.976831John Varghese1958-1698048MiAaPQMiAaPQMiAaPQBOOK9910810075403321BACE4079228UNINA