The selective BACE1 inhibitor VIa reduces Aβ production in a mouse model of Alzheimer’s disease (846.4)

We are pursuing potentβ‐site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors in an effort to identify suitable Alzheimer’s disease (AD) drug candidates. Employing a homogeneous, time‐resolved fluorescence technique, we determined the selectivity of compound VIa. We then conducted a cell‐based assay using the huAPPswe/huBACE1 transgenic CHO cell to investigate the effect on the β‐cleavage of APP. The effect of VIa anti‐AD was valued using both acute and subchronic dosing paradigms in PrPhAPPswe/PS1ΔE9 transgenic mice. Our results have shown that the novel compound VIa exhibits potent inhibitory effects with and IC50=5.9 nM and displays 30.8‐fold, 7500‐fold and 17533‐fold selectivity against the other aspartic proteases BACE2, cathepsin D and renin, respectively. In cellular assays, VIa moderately reduces Aβ production: Aβ1‐40 with an IC50 =143 nM and 1 nM VIa reduced Aβ1‐42 by 40.17%. Concomitant with VIa inhibiting the β‐cleavage of amyloid precursor protein (APP), VIa increases the production of sAPPα with an approximate EC50 of 16.5 nM. In testing this compound’s efficacy in vivo, the oral administration of VIa resulted in a significant decrease in Aβ1‐40 and Aβ1‐42 in the blood of a mouse model of AD by 17.5‐72.44% and 14.5‐80.32%, respectively. This result indicates that the novel compound VIa is a small, potent, selective, and nonpeptidic BACE1 inhibitor. Grant Funding Source : the National Science and Technology Major Project (2012ZX09301003‐002‐001, 2013ZX09508104)