Back to Search
Start Over
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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2010 Dec 09; Vol. 53 (23), pp. 8298-308. Date of Electronic Publication: 2010 Nov 10. - Publication Year :
- 2010
-
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.
- Subjects :
- Animals
Biological Availability
Humans
Indoles pharmacology
Inhibitory Concentration 50
Magnetic Resonance Spectroscopy
Mice
Mice, Inbred C57BL
Oxadiazoles chemistry
Phospholipase A2 Inhibitors chemistry
Phospholipase A2 Inhibitors pharmacokinetics
Solubility
Spectrometry, Mass, Electrospray Ionization
Group IV Phospholipases A2 antagonists & inhibitors
Indoles chemistry
Oxadiazoles pharmacology
Phospholipase A2 Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 53
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 21067218
- Full Text :
- https://doi.org/10.1021/jm101094p