Design of pentapeptidic BACE1 inhibitors with carboxylic acid bioisosteres at image and P4 positions Original Research Article

We previously reported potent BACE1 inhibitors KMI-420 and KMI-570 possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. Acidic moieties at the image and P4 positions of KMI inhibitors are thought to be unfavorable in terms of membrane permeability across the blood–brain barrier. Herein, we replaced acidic moieties at the P4 position with hydrogen bond accepting groups and acidic moieties at the image position with less acidic and similar molecular-size moieties (carboxylic acid or tetrazole bioisosteres). These inhibitors exhibited improved BACE1 inhibitory activities and a thorough quantitative structure–activity relationship study was performed.