Stereoselective Inhibition of Inducible Cyclooxygenase by Chiral Nonsteroidal Antiinflammatory Drugs.

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 μmol/L). In contrast, both isoenzymes were inhibited less than 40% by all three R- enantiomers at high concentration (>1 μmol/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 μmol/L) with slightly less potency than S- ketorolac (IC₅₀ = 0.9 μmol/L) and S-flurbiprofen (IC₅₀ = 0.48 μmol/L), whereas the R- enantiomers were found to be essentially inactive (IC₅₀ ≥ 80 μmol/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. [ABSTRACT FROM AUTHOR]