Varghese John

BACE (eBook, PDF)

Lead Target for Orchestrated Therapy of Alzheimer's Disease

• Format: PDF

Produktbeschreibung

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

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Produktdetails

• Verlag: John Wiley & Sons
• Seitenzahl: 272
• Erscheinungstermin: 31. März 2010
• Englisch
• ISBN-13: 9780470594070
• Artikelnr.: 37297502

Autorenporträt

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.

Inhaltsangabe

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
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 ß-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 ß-Secretase: Discovery, Function, and Inhibitors
10.3 Generation of Aß Peptides via the Endocytic Pathway
10.4 Generation of Anti-APP ß-Site Antibodies
10.5 Antibody Interference with Aß Production in Cellular Model
10.6 Antibody Interference with Aß Production in Animal Models
10.7 Identification of APP Binding Small Molecules that Block ß-Site
Cleavage of APP
10.8 Final Remarks
AFTERWORD
Ruth Abraham)
Introduction
Artwork as a Measure of the Progression of AD
INDEX