Normal-phase HPLC and HPLC-MS studies of the metabolism of a cytosolic phospholipase A(2)alpha inhibitor with activated ketone group by rat liver microsomes.
Inhibition of cytosolic phospholipase A(2)alpha (cPLA(2)alpha) 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 cPLA(2)alpha. 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/MS(n).
Fabian
Jörg
J
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
Lehr
Matthias
M
D000438:Alcohols / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism* / Q000494:pharmacology; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004791:Enzyme Inhibitors / Q000378:metabolism; D054513:Group IV Phospholipases A2; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D007659:Ketones / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*; D013056:Spectrophotometry, Ultraviolet / Q000379:methods
C518325:1-(3-(4-octylphenoxy)-2-oxopropyl)indole-5-carboxylic acid; D000438:Alcohols; D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D007659:Ketones; D010741:Phospholipases A; D054513:Group IV Phospholipases A2