Jpn. J. Pharmacol. 85 (2), 175-182 (2001)

The Anti-inflammatory Effect of FR188582, a Highly Selective Inhibitor of Cyclooxygenase-2, With an Ulcerogenic Sparing Effect in Rats

Takehiro Ochi1,*, Aiko Yamane-Sugiyama2, Yoshitaka Ohkubo1, Kazuo Sakane3 and Hirokazu Tanaka2

1Department of Immunology and Inflammation, Medicinal Biology Research Laboratories, 2Research Information Management Division, and 3Medicinal Chemistry Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., 1-6, Kashima 2-chome, Yodogawa-ku, Osaka 532-8514, Japan
*Corresponding author. FAX: +81-6-6304-5367

Abstract: The anti-inflammatory and ulcerogenic effects of FR188582, 3-chloro-5-[4-(methylsulfonyl)phenyl]-1-phenyl-1H-pyrazole, were investigated. In a recombinant human cyclooxygenase (COX) enzyme activity, FR188582 inhibited COX-2 with an IC50 value of 0.017 mM, and the inhibition of prostaglandin (PG) E2 formation by FR188582 was over 6000 times more selective for COX-2 than COX-1. 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 immunoreactive PGE2, but not immunoreactive leukotriene (LT) B4, in arthritic paw. Unlike indomethacin, FR188582 did not induce visible gastric lesions in rats at doses up to 32 mg/kg, p.o. Furthermore, FR188582 did not inhibit the level of immunoreactive PGE2 and immunoreactive 6-keto PGF1a in rat gastric mucosa. These results suggest that FR188582, a highly selective COX-2 inhibitor, has a potent anti-inflammatory effect mediated by inhibition of PGE2 in inflamed tissues. The safety profile of FR188582 appears to be improved over the safety profile of indomethacin.

Keywords: FR188582, Cyclooxygenase-2, Adjuvant arthritis, PGE2 formation, Gastric lesion

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