BACE: Lead Target for Orchestrated Therapy of Alzheimer's Disease

BACE inhibitors and their use in the treatment of Alzheimer's Disease BACE (β-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 APP By 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.

Table of Contents:
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 Aβ 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 β-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 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 Andreas Kuglstatter and Michael Hennig 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 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 and Nonpeptidomimetics 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 Aging and 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 Ishrut Hussain and Emmanuel Demont 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 Henry H. Hsu 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 Remarks CHAPTER 10 FUTURE STRATEGIES FOR DEVELOPMENT OF NOVEL BACE INHIBITORS: ANTI-APP β-SITE ANTIBODY AND APP BINDING SMALL MOLECULE APPROACHES FOR ALZHEIMER'S DISEASE Beka Solomon, Michal Arbel-Ornath, Clare Peters-Libeu, and Varghese John 10.1 Introduction 10.2 β-Secretase: Discovery, Function, and Inhibitors 10.3 Generation of Aβ Peptides via the Endocytic Pathway 10.4 Generation of Anti-APP β-Site Antibodies 10.5 Antibody Interference with Aβ Production in Cellular Model 10.6 Antibody Interference with Aβ Production in Animal Models 10.7 Identification of APP Binding Small Molecules that Block β-Site Cleavage of APP 10.8 Final Remarks AFTERWORD Ruth Abraham) Introduction Artwork as a Measure of the Progression of AD INDEX

About the Author :
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.

Review :
"Overall this book is a timely and comprehensive resource covering developments in BACE-targeted therapeutic agents from infancy to the present time. It will prove to be valuable to researchers working in the AD field, as well as to medicinal chemists seeking to learn more about rational design of aspartyl protease inhibitors." (ChemMedChem, November 2010)