1-(5-Carboxyindol-1-yl)propan-2-one Inhibitors of Human Cytosolic Phospholipase A₂α: Effect of Substituents in Position 3 of the Indole Scaffold on Inhibitory Potency, Metabolic Stability, Solubility, and Bioavailability

Abstract

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.

Mechanistic Studies for Synthesis of Bis(indolyl)methanes: Pd-Catalyzed C–H Activation of Indole–Carboxylic Acids with Benzyl Alcohols in Water

“…Itoh and co-workers reported the only one-pot synthesis from indole-3-butyric acid with benzyl alcohols using catalytic iodine and oxygen under visible light irradiation [42]. Indole carboxylic acids and their analogs are key units in a wide range of relevant pharmacophores with a broad spectrum of activities [41][42][43][44][45][46]. In general, almost all of the compounds that have been synthesized based on protection/deprotection steps and known organic transformations tend to be inefficient in organic solvents.…”

Structure–activity relationship studies on 1-heteroaryl-3-phenoxypropan-2-ones acting as inhibitors of cytosolic phospholipase A2αand fatty acid amide hydrolase: replacement of the activated ketone group by other serine traps

“…cPLA 2 a inhibitory potency and metabolic stability in rat liver S9 fractions of (5-carboxyindol-1-yl)propan-2-ones. 12 (CAS 1138028-71-3): 63 ± 6.7 % (n ¼ 9). Table 2.…”

Determination of arachidonic acid by on-line solid-phase extraction HPLC with UV detection for screening of cytosolic phospholipase A2α inhibitors

“…Additionally, three cPLA 2 ␣ inhibitors with indole-5-carboxylic acid scaffold developed in our group [33][34][35] were evaluated. The results are shown in Table 1.…”