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, flurbi profen, and ketorolac- has been investigated. The activity and inhibit ion 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 we re compared with the inhibition of constitutive cyclooxygenase (COX-1) in three parallel in vitro models: clotting guinea pig blood, human p olymorphonuclear leukocytes, and purified COX-1 from ram seminal vesic les. In the whole blood model, both isoenzymes were inhibited by S-ena ntiomers with equal potency but S-ketoprofen was the most active on CO X-2 (IC50 = 0.024 mu mol/L). In contrast, both isoenzymes were inhibit ed less than 40% by all three R-enantiomers at high concentration (>1 mu mol/L). The inhibition of COX by the R-enantiomers may be attribute d to contamination with the S-enantiomers (approximately 0.5%). A sign ificant degree of enantioselectivity in COX-2 inhibition was also obse rved 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-fol d more potent than the corresponding R-enantiomers. Finally, S-ketopro fen inhibited COX-2 from sheep placenta (IC50 = 5.3 mu mol/L) with sli ghtly less potency than S-ketorolac (IC50 = 0.9 mu mol/L) and S-flurbi profen (IC50 = 0.48 mu mol/L), whereas the R-enantiomers were found to be essentially inactive (IC50 2 greater than or equal to 80 mu mol/L) . It is concluded that the chiral NSAIDs studied here inhibit with com parable stereoselectivity both COX-2 and COX-1 isoenzymes, and that th e inhibition of COX-2 previously observed for racemic NSAIDs should be attributed almost exclusively to their S-enantiomers.