The anti-inflammatory effect of FR188582, a highly selective inhibitor of cyclooxygenase-2, with an ulcerogenic sparing effect in rats

The anti-inflammatory and ulcerogenic effects of FR188582, 3-chloro-5-[4-(m ethylsulfonyl) phenyl]-1-phenyl-1H-pyrazole, were investigated. Un a recomb inant human cyclooxygenase (COX) enzyme activity, FR188582 inhibited COX-2 with an IC50 value of 0.017 muM, and the inhibition of prostaglandin (PG) E -2 formation by FR188582 was over 6000 times more selective for COX-2 than COX-I. Oral administration of FR188582 dose-dependently inhibited adjuvant arthritis. This effect was threefold more potent than that of indomethacin. FR188582 and indomethacin dose-dependently suppressed the formation of imm unoreactive PGE(2), but not immunoreactive leukotriene (LT) B-4, in arthrit ic paw. Unlike indomethacin, FR188582 did not induce visible gastric lesion s in rats at doses up to 32 mg/kg, p.o. Furthermore, FR188582 did not inhib it the level of immunoreactive PGE(2) and immunoreactive 6-keto PGF(1 alpha ) in rat gastric mucosa. These results suggest that FR188582, a highly sele ctive COX-2 inhibitor, has a potent anti-inflammatory effect mediated by in hibition of PGE(2) in inflamed tissues. The safety profile of FR188582 appe ars to be improved over the safety profile of indomethacin.