beta-Secretase inhibitors: modification at the P4 position and improvement of inhibitory activity in cultured cells |
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| Authors: | Hamada Yoshio Igawa Naoto Ikari Hayato Ziora Zyta Nguyen Jeffrey-Tri Yamani Abdellah Hidaka Koushi Kimura Tooru Saito Kazuki Hayashi Yoshio Ebina Maiko Ishiura Shoichi Kiso Yoshiaki |
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| Institution: | Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Japan. |
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| Abstract: | Recently, we reported potent and small-sized beta-secretase (BACE1) inhibitors KMI-570 and KMI-684 in which we replaced carboxylic acid groups at the P(1)(') 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 P(4) 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. |
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