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
E-mail: takehiro_ochi@po.fujisawa.co.jp
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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