BACE (Beta-Amyloid site Cleaving Enzyme; ß-Secretase) inhibitors for the treatment of Alzheimer's disease

MEDI 244

Ellen W. Baxter, ebaxter@prdus.jnj.com1, Richard S. Alexander2, Scott A. Ballentine2, Francois P. Bischoff2, Robert E. Boyd2, Mirielle Braeken2, Douglas E. Brenneman2, Steven J. Coats2, Kelly A. Conway2, Andrew L. Darrow2, Hans De Winter2, Yifang Huang2, Sergey E. Ilyin2, Alfonzo D. Jordan2, Ludo E. J. Kennis, ludo.kennis@pandora.de2, Chi Luo2, Marc H. Mercken2, Serge M. A. Pieters2, Junya Qu2, Jennifer A. Piesvaux2, Charles H. Reynolds2, Mark J. Schulz2, Malcolm K. Scott2, Christopher A. Teleha2, Brett A. Tounge2, and Allen B. Reitz2. (1) Johnson & Johnson Pharmaceutical R&D, Welsh and McKean Roads, PO Box 776, Spring House, PA 19477-0776, (2) Johnson & Johnson Pharmaceutical R&D LLC, Welsh and McKean Roads, PO Box 776, Spring House, PA 19477-0776
Alzheimer's Disease (AD) currently affects four million Americans and is a growing medical concern with the increasing percentage of elderly in the population. The amyloid hypothesis has been proposed to explain the etiology of AD; ß-secretase (BACE) and γ-secretase cleave the amyloid precursor protein (APP) at the N- and C-terminus, respectively, to provide ß-amyloid peptides, Aß1-40 and Aß1-42, which aggregate into neurotoxic oligomers and fibrils. As a disease-modifying approach to AD, we initiated a program to discover and design novel BACE inhibitors. After a high throughput screen of the Johnson & Johnson PRD compound collection, several low micromolar inhibitors of BACE were identified. The most promising hit had Ki = 1 uM, and was crystallized in the active site of BACE. The X-ray structure of this compound in BACE was used to guide the design of more potent inhibitors, and the best have Kis in the single digit nanomolar range.
 

Abeta Production Inhibitors: Progress Toward a Clinical Test of the Amyloid Hypothesis
9:00 AM-12:00 PM, Wednesday, August 22, 2007 BCEC -- 210 B/C, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007