BACE1 inhibitors: Optimization by replacing the [View the MathML source] 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 A beta production in vivo. However, acidic moieties at the P sub(4) and [View the MathML source] positions of KMI-compounds were thought to be unfavorable for membrane permeability across the blood-brain barrier. Herein, we replaced acidic moieties at the P sub(4) 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 [View the MathML source] position with non-acidic and low molecular sized moieties.