2_氨基苯并咪唑类BACE1抑制剂的设计和合成_余家沛_牛彦_孙琦_许凤荣_梁磊.pdfVIP

网络出版时间：2017-09-30 14:55:09 网络出版地址：/kcms/detail/11.2863.R1455.006.html 650 Journal of Chinese Pharmaceutical Sciences Design and synthesis of 2-aminobenzimidazoles as potential BACE1 inhibitors * * Jiapei Yu, Yan Niu , Qi Sun, Fengrong Xu, Lei Liang, Chao Wang, Ping Xu Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China Abstract: Fragment-based drug discovery (FBDD) has been widely applied in the research of aspartyl protease inhibitors. In the present study, we reported our work on 2 -aminobenzimidazole as the original fragment, which was predicted to bind with the catalytic aspartyl dyad (Asp228 and Asp32) of β-site amyloid precursor protein cleaving enzyme 1 (BACE1). A series of novel 2-aminobenzimidazole derivatives were designed and synthesized. The results from FRET assay revealed that three out of the 12 designed 2-aminobenzimidazoles could inhibit more than 50% of the enzymatic potency of BACE1 at 10 μM. Docking study showed that 2-aminobenzimidazole could form multiple hydrogen bonds and occupy S1/S2’ pockets well. Keywords: Alzheimer’s disease; BACE1 inhibitors; FBDD; 2-Aminobenzimidazole CLC number: R916 Document code: A Article ID: 1003– 1057(2017)9–650– 10 1. Introduction In the past two decades, efforts have been devoted to the design of peptidic and peptidomimetic inhibitors. Alzheimer’s dis