PHARMACOLOGY OF A SELECTIVE CYCLOOXYGENASE-2 INHIBITOR, L-745,337 - ANOVEL NONSTEROIDAL ANTIINFLAMMATORY AGENT WITH AN ULCEROGENIC SPARINGEFFECT IN RAT AND NONHUMAN PRIMATE STOMACH

Recent studies have shown that there are two isoforms of cyclooxygenas es. The constitutive form, cyclooxygenase 1 (COX-I), is believed to be involved in the maintenance of physiological functions. A second isof orm, cyclooxygenase 2 (COX-2), has been shown to be induced in inflamm ation. In the present study, the pharmacology of a selective inhibitor of COX-2, L-745,337 ulfonamido-6-(2,4-difluorothiophenyl)-1-indanone) , is described. L-745,337 has IC50 values of 23 +/- 8 nM and >10 mu M for the inhibition of prostaglandin E(2) production in whole-cell assa ys for COX-2 and COX-1, respectively. This compound inhibited carragee nan-induced rat paw edema and rat paw hyperalgesia with ID50 values of 2.00 and 0.37 mg/kg, respectively. In an endotoxin-induced pyresis as say in the rat, L-745,337 significantly reversed the pyretic responses (ID50 = 3.75 mg/kg). L-745,337 did not cause visible gastric lesions in rats at up to 30 mg/kg (4 hr after dosing). In a fecal (51)chromium (Cr-51) excretion assay to detect gastrointestinal integrity in rats and primates, L-745,337 had no effect at doses up to 100 mg/kg (rat) o r after chronic dosing at 20 mg/kg per day for 5 days (primates). In c ontrast, oral administration of indomethacin, diclofenac or flurbiprof en resulted in substantial increase in fecal Cr-51 excretion and/or fr ank gastric ulceration (rats). L-745,337 significantly inhibited the p rostaglandin E(2) levels in the inflammatory exudates from the rat ple ural cavity after injection with carrageenan but did not inhibit prost aglandin E(2) levels in the stomach. These results suggest that the CO X-2 inhibitor L-745,337 is a novel anti-inflammatory, antipyretic and analgesic compound with no demonstrable ulcerogenic effects. Selective COX-2 inhibitors may therefore represent a new class of novel nonster oidal anti-inflammatory agents (NSAIDs) with greatly improved safety p rofiles over currently available nonselective NSAIDs.