Anti-inflammatory effect of FR140423, a novel selective cyclo-oxygenase-2 inhibitor, in rat adjuvant arthritis without gastrointestinal side effects

We investigated the effect of FR140423 (3-(difluoromethyl)-1-(4-methoxyphen yl)-5-[4-(methylsulphinyl)phenyl]pyrazole), a novel and selective cyclo-oxy genase (COX)-2 inhibitor, in rat adjuvant arthritis. The results were compa red with that of indomethacin. We tested the inhibitory effects of FR140423 on paw oedema and the formatio n of the arachidonic acid metabolites prostaglandin (PG) E-2 and leukotrien e (LT) B-4 in inflamed paws immunized with heat-killed and dried Mycobacter ium tuberculosis. Oral administration of FR140423 showed a dose-dependent a nti-inflammatory effect. This effect was two- to threefold more potent than that of indomethacin. The increase of PGE(2) and LTB4 in inflamed paws was associated with the development of paw swelling. FR140423 and indomethacin dose-dependently suppressed the level of PGE(2) but not LTB4 in arthritic paws. Unlike indomethacin, FR140423 did not induce gastric lesions even at doses up to 10 mg kg(-1) in arthritic rats. FR140423 has a potent anti-inflammatory effect mediated by inhibition of PG E(2) produced by COX-2 in inflamed tissues. The safety profile of FR140423 appears to be an improvement on the safety profile of indomethacin.