Department of Medicinal Chemistry, Centre for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto, Japan.
Bioorg Med Chem. 2011 Sep 1;19(17):5238-46. doi: 10.1016/j.bmc.2011.07.002. Epub 2011 Jul 13.
Previously, we reported potent pentapeptidic BACE1 inhibitors with the hydroxymethylcarbonyl isostere as a substrate transition-state mimic. To improve the in vitro potency, we further reported pentapeptidic inhibitors with carboxylic acid bioisosteres at the P(4) and P1' positions. In the current study, we screened new P1' position 1-phenylcycloalkylamine analogs to find non-acidic inhibitors that possess double-digit nanomolar range IC(50) values. An extensive structure-activity relationship study was performed with various amine derivatives at the P1' position. The most potent inhibitor of this pentapeptide series, KMI-1830, possessing 1-phenylcyclopentylamine at the P1' position had an IC(50) value of 11.6 nM against BACE1 in vitro enzymatic assay.
此前，我们报道了具有羟甲基羰基等排体的强效五肽 BACE1 抑制剂作为底物过渡态模拟物。为了提高体外活性，我们进一步报道了在 P(4)和 P1'位具有羧酸生物等排体的五肽抑制剂。在本研究中，我们筛选了新的 P1'位 1-苯基环烷基胺类似物，以寻找具有双位数纳摩尔范围 IC(50)值的非酸性抑制剂。在 P1'位用各种胺衍生物进行了广泛的构效关系研究。该五肽系列中最有效的抑制剂 KMI-1830，在体外酶测定中对 BACE1 的 IC(50)值为 11.6 nM，其 P1'位具有 1-苯基环戊基胺。
