Stereoselective Inhibition of Inducible Cyclooxygenase by Chiral Nonsteroidal Antiinflammatory Drugs

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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.

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