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
Ellen W. Baxter, Kelly A. Conway, Ludo E. J. 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 Pieters, Didier Berthelot, Stefan Masure, Wouter Bruinzeel, Alfonzo D. Jordan, Michael H. Parker, Robert E. Boyd, Junya Qu · Journal of Medicinal Chemistry · 2007
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 (Asp(32), Asp(228)). BACE-1 inhibitory potency was increased (0.9 microM to 11 nM K(i)) by substitution into the unoccupied S(1)' pocket.