Differential effect of FR122047, a selective cyclo-oxygenase-1 inhibitor, in rat chronic models of arthritis

Abstract

1. We investigated the effects of FR122047 (1-[(4,5-bis(4-methoxyphenyl)-2-thiazoyl)carbonyl]-4-methylpiperazine hydrochloride), a selective cyclo-oxygenase (COX)-1 inhibitor, in rat type II collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA). 2 Using an ex vivo rat whole blood assay, FR122047 (0.032-3.2 mg kg-1) inhibited COX-1-derived thromboxane (TX) B2 production with ED50 value of 0.059 mg kg-1, indicating that it was orally active, but did not inhibit lipopolysaccharide-induced prostaglandin (PG) E2 production derived by COX-2. 3 Oral administration of FR122047 showed a dose-dependent anti-inflammatory effect in rat CIA with ED50 value of 0.56 mg kg-1. This drug also dose dependently suppressed the levels of PGE2 and TXB2 in CIA rat paws with ED50 values of 0.24 and 0.13 mg kg-1, respectively. 4 FR122047 had no effect in rat AIA model. In contrast, indomethacin, a non-selective COX inhibitor, was anti-inflammatory and reduced the formation of PGs in AIA rat paws. 5 Unlike indomethacin, chronic treatment of FR122047 did not damage the stomach mucosa in CIA rats. 6 These results demonstrate that COX-1 contributes to the oedema and the formation of PGE2 and TXB2 in rat CIA model, but not in rat AIA model. 7. We conclude that FR122047 has an orally active and anti-inflammatory effect mediated by inhibition of PGE2 and TXB2 produced by COX-1 at a site of inflammation induced by type II collagen and it may be a useful tool for studying the involvement of COX-1 in various in vivo models of inflammation.