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

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 P4 position of KMI-260 and KMI-360, respectively, with a 1H-tetrazole-5-carbonyl DAP (l-α,β-diaminopropionic acid) residue. At the 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 carboxylic acid bioisosteres in order to develop practical anti-Alzheimer’s disease drugs. Among them, tetrazole ring-containing compounds, KMI-570 (IC50 = 4.8 nM) and KMI-684 (IC50 = 1.2 nM), exhibited significantly potent BACE1 inhibitory activities.