BACE

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.

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