1. Edition - March 2010
87.90 Euro
2010. 250 Pages, Hardcover
- Monograph -
ISBN-10: 0-470-29342-X
ISBN-13: 978-0-470-29342-3 - John Wiley & Sons






Sample Chapter

Short 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.

From the 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 A².

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 2-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 Classifi cation.

3.5 BACE Structure.

3.6 Mechanism, Kinetics, Inhibition, and Specifi city.

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 Identifi ed 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 Effi cacy 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 2-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 2-Secretase: Discovery, Function, and Inhibitors.

10.3 Generation of A² Peptides via the Endocytic Pathway.

10.4 Generation of Anti-APP 2-Site Antibodies.

10.5 Antibody Interference with A² Production in Cellular Model.

10.6 Antibody Interference with A² Production in Animal Models.

10.7 Identifi cation of APP Binding Small Molecules that Block 2-Site Cleavage of APP.

10.8 Final Remarks.

AFTERWORD (Ruth Abraham).

Introduction.

Artwork as a Measure of the Progression of AD.

INDEX.