Normal-phase HPLC and HPLC-MS studies of the metabolism of a cytosolic phospholipase A2α inhibitor with activated ketone group by rat liver microsomes

Fabian J, Lehr M

Abstract

Inhibition of cytosolic phospholipase A2α (cPLA2α) is assumed to provide a novel therapeutic approach for the treatment of many inflammatory diseases. 1-[3-(4-Octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (2) is a potent inhibitor of cPLA2α. An important part of the pharmacophore of 2 is its activated electrophilic ketone moiety. Since it is known that activated ketones may be metabolically unstable, the metabolism of 2 by rat liver microsomes was investigated. For quantification of the metabolites normal-phase HPLC/UV on a cyano column was used, because under reversed-phase conditions with aqueous solvents 2 was partly transformed into its hydrate resulting in chromatograms with splitted peaks. Under the conditions applied about 30% of 2 were metabolized. The main metabolite was the alcohol 4 as shown by LC/MSn.