BACE1 inhibitors: Optimization by replacing the residue with non-acidic moiety

Recently, we reported potent BACE1 inhibitors KMI-429, -684, and -574 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays, especially, KMI-429 was confirmed to significantly inhibit Aβ production in vivo. However, acidic moieties at the P4 and positions of KMI-compounds were thought to be unfavorable for membrane permeability across the blood–brain barrier. Herein, we replaced acidic moieties at the P4 position with other hydrogen bond acceptor groups, and these inhibitors exhibited improved BACE1 inhibitory activities in cultured cells. In this study, we replaced the acidic moieties at the position with non-acidic and low molecular sized moieties.