Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 18, Issue 5, Pages 1649-1653Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2008.01.058
Keywords
Alzheimer's disease; BACE1; beta-secretase; BACE1 inhibitor
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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-4 and P-1' 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-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 P-1' position with non-acidic and low molecular sized moieties. (c) 2008 Elsevier Ltd. All rights reserved.
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