jm0705408_si_001.pdf (592.58 kB)

2-Amino-3,4-dihydroquinazolines as Inhibitors of BACE-1 (β-Site APP Cleaving Enzyme):  Use of Structure Based Design to Convert a Micromolar Hit into a Nanomolar Lead

Download (592.58 kB)
journal contribution
posted on 06.09.2007, 00:00 by Ellen W. Baxter, Kelly A. Conway, Ludo Kennis, François Bischoff, Marc H. Mercken, Hans L. De Winter, Charles H. Reynolds, Brett A. Tounge, Chi Luo, Malcolm K. Scott, Yifang Huang, Mirielle Braeken, Serge M. A. Pieters, Didier J. C. Berthelot, Stefan Masure, Wouter D. Bruinzeel, Alfonzo D. Jordan, Michael H. Parker, Robert E. Boyd, Junya Qu, Richard S. Alexander, Douglas E. Brenneman, Allen B. Reitz
A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp32, Asp228). BACE-1 inhibitory potency was increased (0.9 μM to 11 nM Ki) by substitution into the unoccupied S1‘ pocket.