Design and synthesis of potent beta-secretase (BACE1) inhibitors with P1' carboxylic acid bioisosteres |
| |
Authors: | Kimura Tooru Hamada Yoshio Stochaj Monika Ikari Hayato Nagamine Ayaka Abdel-Rahman Hamdy Igawa Naoto Hidaka Koushi Nguyen Jeffrey-Tri Saito Kazuki Hayashi Yoshio Kiso Yoshiaki |
| |
Institution: | Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan. |
| |
Abstract: | Recently, we reported potent and small-sized beta-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-alpha,beta-diaminopropionic acid) residue. At the P1' 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 P1' 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. |
| |
Keywords: | |
本文献已被 ScienceDirect PubMed 等数据库收录! |
|