Design and synthesis of potent β-secretase (BACE1) inhibitors with [formula omitted] carboxylic acid bioisosteres

Abstract

Recently, we reported potent and small-sized β-secretase (BACE1) inhibitors KMI-420 and KMI-429 in which we replaced the Glu residue at the P 4 position of KMI-260 and KMI-360, respectively, with a 1 H-tetrazole-5-carbonyl DAP ( l-α,β-diaminopropionic acid) residue. At the P 1 ′ position, these compounds contain one or two carboxylic acid groups, which are unfavorable for crossing the blood–brain barrier. Herein, we report BACE1 inhibitors with P 1 ′ carboxylic acid bioisosteres in order to develop practical anti-Alzheimer’s disease drugs. Among them, tetrazole ring-containing compounds, KMI-570 (IC 50 = 4.8 nM) and KMI-684 (IC 50 = 1.2 nM), exhibited significantly potent BACE1 inhibitory activities.