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.
Bioorg Med Chem. 2013 Nov 1;21(21):6665-73. doi: 10.1016/j.bmc.2013.08.016. Epub 2013 Aug 12.
We have reported potent peptidic and non-peptidic BACE1 inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. However, our potent inhibitors possess a tetrazole ring at the P1' position. It is desirable that central nervous system (CNS) drugs do not possess an acidic moiety. In this study, we synthesized non-acidic BACE1 inhibitors with heterocyclic derivatives at the P1' position. KMI-1764 (27) exhibited potent inhibitory activity (IC50=27nM). Interestingly, these non-acidic inhibitors tended to follow the quantitative structure-activity relationship (QSAR) equation and interacted with BACE1-Arg235 in the binding model.
我们曾报道过具有羟甲基羰基（HMC）等排体作为底物过渡态类似物的强效肽类和非肽类 BACE1 抑制剂。然而，我们的强效抑制剂在 P1'位置都具有一个四唑环。中枢神经系统（CNS）药物最好不含有酸性部分。在这项研究中，我们合成了在 P1'位置具有杂环衍生物的非酸性 BACE1 抑制剂。KMI-1764（27）表现出很强的抑制活性（IC50=27nM）。有趣的是，这些非酸性抑制剂似乎遵循定量构效关系（QSAR）方程，并在结合模型中与 BACE1-Arg235 相互作用。
