BACE: Lead Target for Orchestrated Therapy of Alzheimer's Disease / Edition 1

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Overview

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.

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Editorial Reviews

From the Publisher
"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)
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Product Details

  • ISBN-13: 9780470293423
  • Publisher: Wiley
  • Publication date: 3/15/2010
  • Edition number: 1
  • Pages: 266
  • Product dimensions: 6.30 (w) x 9.30 (h) x 0.80 (d)

Meet 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.

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Read an Excerpt

http://catalogimages.wiley.com/images/db/pdf/9780470293423.excerpt.pdf
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Table of Contents

Preface xi

Acknowledgments xiii

Contributors xv

Chapter 1 Bace, App Processing, and Signal Transduction in Alzheimer's Disease Dale E. Bredesen Edward H. Koo 1

1.1 Introduction 1

1.2 BACE Cleavage of App as a Molecular Switching Mechanism 2

1.3 AD: An Imbalance in Cellular Dependence? 3

1.4 BACE Cleavage, Caspase Cleavage, and Neuronal Trophic Dependence 4

1.5 BACE Cleavage of App, Dependence Receptors, and Alzheimer Pathology 5

1.6 Key Mutations Proximal of App Processing to Aβ 9

1.7 Final Remarks 10

Chapter 2 Identification of Bace as a Target in Alzheimer's Disease Robert L. Heinrikson Sukanto Sinha 15

2.1 Introduction 15

2.2 The Search for β-Secretase 17

2.3 Validation of the BACE Target 27

2.4 Final Remarks 28

Chapter 3 Bace Biological Assays Alfredo G. Tomasselli Michael J. Bienkowski 35

3.1 Introduction 35

3.2 Clinical and Physiological Hallmarks of Alzheimer's Disease (AD) 36

3.3 App Processing 36

3.4 Aspartyl Protease Classification 37

3.5 BACE Structure 38

3.6 Mechanism, Kinetics, Inhibition, and Specificity 39

3.7 Assay Strategies for Inhibitor Finding and Development 45

3.8 Common Assays Used to Identify and Study Inhibitors 48

3.9 BACE Assays 50

3.10 Final Remarks 54

Chapter 4 Peptidic, Peptidomimetic, and HTS-Derived Bace Inhibitors James P. Beck Dustin J. Mergott 59

4.1 Introduction 59

4.2 Elan/Pharmacia (Pfizer) 59

4.3 Oklahoma Medical Research Foundation (OMRF)/Multiple Collaborators 70

4.4 Eli Lilly 72

4.5 Merck 74

4.6 GlaxoSmithKline 80

4.7 Schering Plough 82

4.8 Bristol-Myers Squibb 85

4.9 Novartis 87

4.10 Amgen 88

4.11 Wyeth 90

4.12 Final Remarks 94

Chapter 5 Fragment-Based Approaches for Identification of Bace Inhibitors Andreas Kuglstatter Michael Hennig 107

5.1 Introduction 107

5.2 Biophysical Methods Applied to BACE Fragment Screens 108

5.3 BACE Inhibitors Identified by Fragment Screening 110

5.4 Final Remarks 119

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 Alfredo G. Tomasselli 123

6.1 Introduction 123

6.2 Preparation of BACE for Structural Studies 126

6.3 Crystallographic Studies of BACE 130

6.4 Structural Studies with BACE Inhibitors: Peptidomimetics and Nonpeptidomimetics 135

6.5 Computational Approaches 145

6.6 Final Remarks 150

Chapter 7 Pharmacological Models for Preclinical Testing: From Mouse to Dog to Nonhuman Primates Jason L. Eriksen Michael Paul Murphy Elizabeth Head 159

7.1 Introduction 159

7.2 BACE1 and Mouse Models of AD 161

7.3 Testing BACE Inhibitors in the Canine Model of Human Aging and Ad 163

7.4 BACE Inhibitors and Nonhuman Primates 167

7.5 Final Remarks 168

Chapter 8 Adsorption, Distribution, Metabolism, Excretion (ADME), Efficacy, and Toxicology for Bace Inhibitors Ishrut Hussain Emmanuel Demont 177

8.1 Introduction 177

8.2 Development of Bace Inhibitors with Optimized ADME Properties 180

8.3 In Vivo Efficacy of BACE Inhibitors 188

8.4 Toxicology of BACE Inhibitors 192

8.5 Final Remarks 193

Chapter 9 Clinical Trials for Disease-Modifying Drugs Such As Bace Inhibitors Henry H. Hsu 197

9.1 Introduction 197

9.2 Update on Beta-Amyloid Therapies in Clinical Development 198

9.3 Clinical Development of BACE Inhibitors and Other Disease-Modifying Drugs 203

9.4 Final Remarks 212

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 Varghese John 217

10.1 Introduction 217

10.2 β-Secretase: Discovery, Function, and Inhibitors 218

10.3 Generation of Aβ Peptides via the Endocytic Pathway 220

10.4 Generation of Anti-App β-Site Antibodies 221

10.5 Antibody Interference with Aβ Production in Cellular Model 223

10.6 Antibody Interference with Aβ Production in Animal Model 226

10.7 Identification of App Binding Small Molecules that Block β-Site Cleavage of App 228

10.8 Final Remarks 230

Afterword Ruth Abraham 235

Introduction 235

Artwork as a Measure of the Progression of Ad 236

Index 243

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