Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Hittorfstrasse 58-62, 48149 Münster, Germany.
J Med Chem. 2010 Dec 9;53(23):8298-308. doi: 10.1021/jm101094p. Epub 2010 Nov 10.
Indole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position 1 have been found to be potent inhibitors of human cytosolic phospholipase A2α (cPLA2α). In the course of structure-activity relationship studies, we investigated the effect of a substitution of indole 3 position with acyl, alkyl, and oxadiazole residues. The highest increase of inhibitory potency could be achieved by a 3-methyl-1,2,4-oxadiazol-5-yl-moiety. Appropriate compound 40 revealed an IC50 of 0.0021 μM against isolated cPLA2α. In a cellular assay applying human platelets 40 blocked cPLA2α activity even with an IC50 of 0.0006 μM. Metabolic stability and aqueous solubility of the target compounds were also determined. Furthermore, one selected compound was tested for peroral bioavailability in mice.
在位置 1 带有 3-芳氧基-2-氧代丙基残基的吲哚-5-羧酸被发现是人类胞质型磷脂酶 A2α（cPLA2α）的有效抑制剂。在构效关系研究过程中，我们研究了吲哚 3 位取代为酰基、烷基和恶二唑基残基的效果。用 3-甲基-1,2,4-恶二唑-5-基取代基可获得最高的抑制效力的增加。适当的化合物 40 对分离的 cPLA2α 的 IC50 为 0.0021 μM。在应用于人血小板的细胞测定中，40 甚至以 0.0006 μM 的 IC50 阻断 cPLA2α 活性。还确定了目标化合物的代谢稳定性和水溶解度。此外，还在小鼠中测试了一种选定的化合物的口服生物利用度。
