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.
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.
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Hittorfstrasse 58-62, 48149 Münster, Germany.
Stefanie
S
Bovens
Alwine
A
Schulze Elfringhoff
Martina
M
Kaptur
Dirk
D
Reinhardt
Michael
M
Schäfers
Matthias
M
Lehr
D000818:Animals; D001682:Biological Availability; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D064801:Phospholipase A2 Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility; D021241:Spectrometry, Mass, Electrospray Ionization
C587792:3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-(3-(4-octylphenoxy)-2-oxopropyl)indole-5-carboxylic acid; D007211:Indoles; D010069:Oxadiazoles; D064801:Phospholipase A2 Inhibitors; D054513:Group IV Phospholipases A2