Author/Authors :
Yoshio Hamada، نويسنده , , Naoto Igawa، نويسنده , , Hayato Ikari، نويسنده , , Zyta Ziora، نويسنده , , Jeffrey-Tri Nguyen، نويسنده , , Abdellah Yamani، نويسنده , , Koushi Hidaka، نويسنده , , Tooru Kimura، نويسنده , , Kazuki Saito، نويسنده , , Yoshio Hayashi، نويسنده , , Maiko Ebina، نويسنده , , Shoichi Ishiura، نويسنده , , Yoshiaki Kiso، نويسنده ,
Abstract :
Recently, we reported potent and small-sized β-secretase (BACE1) inhibitors KMI-570 and KMI-684 in which we replaced carboxylic acid groups at the position of KMI-420 and KMI-429, respectively, with tetrazole derivatives as carboxylic acid bioisosteres. These modifications improved significantly BACE1 inhibitory activity and chemical stability. In this study, the acidic tetrazole ring of the P4 position of KMI-420 and KMI-570, respectively, was replaced with various hydrogen bond acceptor groups. We found BACE1 inhibitor KMI-574 that exhibited potent inhibitory activity in cultured cells as well as in vitro enzymatic assay.
