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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.

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Enzyme inhibiting activity X 0220 1-(5-Carboxyindol-1-yl)propan-2-ones as Inhibitors of Human Cytosolic Phospholipase A 2 α: Synthesis and Properties of Bioisosteric Benzimidazole, Benzotriazole and Indazole Analogues. -The indole ring system of the cytosolic A2α(cPLA2α) inhibitor (Ia) is replaced by several nitrogen-containing analogues and the effect on the inhibitory potency, metabolic stability, and solubility is studied. The compounds with the highest metabolic stability are compounds (I). (Ib) is about seven--fold more active than the lead compound (Ia). -(BOVENS, S.; KAPTUR, M.; SCHULZE ELFRINGHOFF, A.; LEHR*, M.; Bioorg. Med.