FR167653, a Cytokine Synthesis Inhibitor, Exhibits Anti-Inflammatory Effects Early in Rat Carrageenin-Induced Pleurisy but No Effect Later

Abstract

We prepared a pharmacological profile of FR167653 (1-[7- (4-fluorophenyl)-1,2,3,4-tetrahydro-8-(4-pyridyl) pyrazolo[5,1-c][1,2,4]triazin-2-yl]-2-phenylethanedion sulfate monohydrate), a cytokine synthesis inhibitor, on early (5 h after irritation) and late (14–24 h after irritation) phases of rat carrageenin-induced pleurisy and on mediator-induced plasma exudation, in comparison with that of dexamethasone. In the early phase, FR167653 (30 mg/kg) and dexamethasone (0.3 mg/kg) equipotently suppressed plasma exudation and leukocyte infiltration. Furthermore, both agents significantly lowered the prostanoid levels in the exudate. Expression of cyclooxygenase-2 protein on leukocytes in the early phase of inflammation was not affected by dexamethasone, but it was suppressed by FR167653. However, FR167653 did not significantly affect the leukocyte mRNA level of cyclooxygenase-2. Both agents significantly suppressed the levels of both tumor necrosis factor-α and interleukin-1β. FR167653 had a different pharmacological profile from dexamethasone in the late phase of this model in that, unlike dexamethasone, it did not affect cyclooxygenase-2 expression in mesothelial cells, the 6-keto-prostaglandin F_1α level in the exudate or hyperplasia of mesothelium. Furthermore, unlike dexamethasone, FR167653 did not consistently inhibit mediator-induced plasma exudation. These results suggest that FR167653 or one of its analogs may be new candidates for therapy with a spectrum of activity distinct from that of current anti-inflammatory steroids.