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

Abstract

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 PGE 2, 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 PGF1= 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.

Structural diversity of selective COX-2 inhibitors

“…Examples of central heterocycles include 5-or 6-membered rings that contain one (thiophenes [35][36][37], pyrroles [59][60][61], furans [62,63] and pyridines Pyrroles Eurans 2(5H)-Furanones Thiazo1es 21 [64][65][66]), two (thiazoles [67,68], oxazoles and the corresponding oxazolones [69,70], imidazoles [71][72][73], isoxazoles [74][75][76], pyrazoles [38,[77][78][79]), or three (thiadiazole [80]) heteroatoms (Fig. 6).…”

Antileishmanial and Antibacterial Activity of a New Pyrazole Derivative Designated 4‐[2‐(1‐(Ethylamino)‐2‐methyl‐ propyl)phenyl]‐3‐(4‐methyphenyl)‐1‐phenylpyrazole

“…The medical importance of pyrazole derivatives is indicated by the large number of reports documenting their various biological activities, such as reported antitumor [16 -18], anti-inflammatory [19,20], ulcerogenic [21], antiviral [22], immunosupressant [23], and antimicrobial activities [17, 24 -27]. Some members of this class of compounds have also been investigated for their local anaesthesic and antiarrhythmic [28], herbicidal [29], and molluscicidal [30] properties.…”

Effects of Intravenous Administration of FR122047 (a Selective Cyclooxygenase 1 Inhibitor) and FR188582 (a Selective Cyclooxygenase 2 Inhibitor) on Prostaglandin-E₂-Induced Aqueous Flare Elevation in Pigmented Rabbits

“…The IC 50 values of diclofenac for COX-1 and COX-2 were 1.57 and 1.1 ÌM, respectively [9]. While screening for inhibitors of platelet aggregation, Ochi et al [10][11][12] have found that FR122047 is a selective COX-1 inhibitor and FR188582 is a selective COX-2 inhibitor. The authors further reported that in recombinant human COX enzyme assays, IC 50 values of FR122047 for COX-1 and COX-2 were 0.028 and 65 ÌM, respectively (2,300 times more selective for COX-1 than COX-2), and IC 50 values of FR188582 for COX-1 and COX-2 were 100 and 0.017 ÌM, respectively (over 6,000 times more selective for COX-2 than COX-1) [10,12].…”

“…While screening for inhibitors of platelet aggregation, Ochi et al [10][11][12] have found that FR122047 is a selective COX-1 inhibitor and FR188582 is a selective COX-2 inhibitor. The authors further reported that in recombinant human COX enzyme assays, IC 50 values of FR122047 for COX-1 and COX-2 were 0.028 and 65 ÌM, respectively (2,300 times more selective for COX-1 than COX-2), and IC 50 values of FR188582 for COX-1 and COX-2 were 100 and 0.017 ÌM, respectively (over 6,000 times more selective for COX-2 than COX-1) [10,12]. In the present study, we examined in vivo effects of the intravenous administration of FR122047 and FR188582 on PGE 2 -induced aqueous flare elevation and mRNA levels for COX-1 and COX-2 in the iris-ciliary body after treatment by these agents in pigmented rabbits.…”