【文章名】1-(5-Carboxyindol-1-yl)propan-2-one Inhibitors of Human Cytosolic Phospholipase A(2)alpha.: Effect of Substituents in Position 3 of the Indole Scaffold on Inhibitory Potency, Metabolic Stability, Solubility, and Bioavailability
1-(5-Carboxyindol-1-yl)propan-2-one Inhibitors of Human Cytosolic Phospholipase A(2)alpha.: Effect of Substituents in Position 3 of the Indole Scaffold on Inhibitory Potency, Metabolic Stability, Solubility, and Bioavailability
[摘要]：Indole-5-carboxylic acids with 3-aryloxy-2-oxopropyl residues in position I have been found to be potent inhibitors of human cytosolic phospholipase A(2)alpha (cPLA(2)alpha). 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 mu M against isolated cPLA(2)alpha. In a cellular assay applying human platelets 40 blocked cPLA(2)alpha. activity even with an IC50 of 0.0006 mu M. Metabolic stability and aqueous solubility of the target compounds were also determined. Furthermore, one selected compound was tested for peroral bioavailability in mice.
