Main description:

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. This 360 degree resource provides every member of the diverse drug-discovery team with global understanding essential for productive and successful drug discovery. It also offers researchers and clinicians an overview of the groundbreaking progress that has been made to develop inhibitors of BACE as efficacious treatments for Alzheimer's disease.

Contents:

PREFACE. ACKNOWLEDGMENTS. CONTRIBUTORS. CHAPTER 1 BACE, APP PROCESSING, AND SIGNAL TRANSDUCTION INALZHEIMER'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 TrophicDependence. 1.5 BACE Cleavage of APP, Dependence Receptors, and AlzheimerPathology. 1.6 Key Mutations Proximal of APP Processing to A . 1.7 Final Remarks. CHAPTER 2 IDENTIFICATION OF BACE AS A TARGET IN ALZHEIMER'SDISEASE (Robert L. Heinrikson and Sukanto Sinha). 2.1 Introduction. 2.2 The Search for -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 sDisease (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 BACEINHIBITORS (James P. Beck and Dustin J. Mergott). 4.1 Introduction. 4.2 Elan/Pharmacia (Pfizer). 4.3 Oklahoma Medical Research Foundation (OMRF)/MultipleCollaborators. 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 OFBACE INHIBITORS (Andreas Kuglstatter and MichaelHennig). 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-DIMENSIONALSTRUCTURE, AND COMPUTATIONAL ANALYSIS (Felix F. Vajdos,Veerabahu Shanmugasundaram, and Alfredo G. Tomasselli). 6.1 Introduction. 6.2 Preparation of BACE for Structural Studies. 6.3 Crystallographic Studies of BACE. 6.4 Structural Studies with BACE Inhibitors: Peptidomimetics andNonpeptidomimetics. 6.5 Computational Approaches. 6.6 Final Remarks. CHAPTER 7 PHARMACOLOGICAL MODELS FOR PRECLINICAL TESTING:FROM MOUSE TO DOG TO NONHUMAN PRIMATES (Jason L. Eriksen,Michael Paul Murphy, and Elizabeth Head). 7.1 Introduction. 7.2 BACE1 and Mouse Models of AD. 7.3 Testing BACE Inhibitors in the Canine Model of Human Agingand AD. 7.4 BACE Inhibitors and Nonhuman Primates. 7.5 Final Remarks. CHAPTER 8 ADSORPTION, DISTRIBUTION, METABOLISM, EXCRETION(ADME), EFFICACY, AND TOXICOLOGY FOR BACE INHIBITORS (IshrutHussain and Emmanuel Demont). 8.1 Introduction. 8.2 Development of BACE Inhibitors with Optimized ADMEProperties. 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 ASBACE INHIBITORS (Henry H. Hsu). 9.1 Introduction. 9.2 Update on Beta-Amyloid Therapies in ClinicalDevelopment. 9.3 Clinical Development of BACE Inhibitors and OtherDisease-Modifying Drugs. 9.4 Final Remarks. CHAPTER 10 FUTURE STRATEGIES FOR DEVELOPMENT OF NOVEL BACEINHIBITORS: ANTI-APP -SITE ANTIBODY AND APP BINDING SMALLMOLECULE APPROACHES FOR ALZHEIMER'S DISEASE (Beka Solomon,Michal Arbel-Ornath, Clare Peters-Libeu, and VargheseJohn). 10.1 Introduction. 10.2 -Secretase: Discovery, Function, and Inhibitors. 10.3 Generation of A Peptides via the EndocyticPathway. 10.4 Generation of Anti-APP -Site Antibodies. 10.5 Antibody Interference with A Production in CellularModel. 10.6 Antibody Interference with A Production in AnimalModels. 10.7 Identification of APP Binding Small Molecules that Block -Site Cleavage of APP. 10.8 Final Remarks. AFTERWORD (Ruth Abraham). Introduction. Artwork as a Measure of the Progression of AD. INDEX.