The selective BACE1 inhibitor VIa reduces amyloid-β production in cell and mouse models of Alzheimer's disease.

β-site amyloid-β protein precursor cleaving enzyme 1 (BACE1) is the first protease and the rate limiting enzyme in the genesis of amyloid-β (Aβ). This protein remains an important potential disease-modifying target for the development of drugs to treat Alzheimer's disease (AD). We are pursuing potent BACE1 inhibitors in an effort to identify suitable AD drug candidates. Our results have shown that the novel compound VIa exhibits potent inhibitory effects with 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: Aβ(1-40) with an IC50 = 143 nM and 1 nM VIa reduced Aβ(1-42) by 40.17%. Concomitant with VIa inhibiting the β-cleavage of amyloid-β protein precursor (AβPP), VIa increases the production of sAβPPα 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 Aβ(1-40) and Aβ(1-42) in the blood of a mouse model of AD by 17.5-72.44% and 14.5-80.32%, respectively. This indicates that the novel compound VIa is a small, potent, selective, and non-peptidic BACE1 inhibitor.