The stereoselective inhibition of inducible cyclooxygenase (COX-2) by chiral nonsteroidal antiinflammatory drugs (NSAIDs)--ketoprofen, flurbiprofen, and ketorolac--has been investigated. The activity and inhibition of COX-2 was assessed in three different in vitro systems: guinea pig whole blood, lipopolysaccharide (LPS)-stimulated human monocytes, and purified preparations of COX-2 from sheep placenta. The results were compared with the inhibition of constitutive cyclooxygenase (COX-1) in three parallel in vitro models: clotting guinea pig blood, human polymorphonuclear leukocytes, and purified COX-1 from ram seminal vesicles. In the whole blood model, both isoenzymes were inhibited by S-enantiomers with equal potency but S-ketoprofen was the most active on COX-2 (IC50 = 0.024 mumol/L). In contrast, both isoenzymes were inhibited less than 40% by all three R-enantiomers at high concentration (> 1 mumol/L). The inhibition of COX by the R-enantiomers may be attributed to contamination with the S-enantiomers (approximately 0.5%). A significant degree of enantioselectivity in COX-2 inhibition was also observed in intact cells. The S-enantiomers inhibited COX-2 from monocytes with IC50 values in the range of 2 to 25 nmol/L, being 100 to 500-fold more potent than the corresponding R-enantiomers. Finally, S-ketoprofen inhibited COX-2 from sheep placenta (IC50 = 5.3 mumol/L) with slightly less potency than S-ketorolac (IC50 = 0.9 mumol/L) and S-flurbiprofen (IC50 = 0.48 mumol/L), whereas the R-enantiomers were found to be essentially inactive (IC50 > or = 80 mumol/L). It is concluded that the chiral NSAIDs studied here inhibit with comparable stereoselectivity both COX-2 and COX-1 isoenzymes, and that the inhibition of COX-2 previously observed for racemic NSAIDs should be attributed almost exclusively to their S-enantiomers.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.