THU0088 Prevention of a novel and newly discovered anti-arthritic compound sx-5452 on development of collagen-induced arthritis in dba/1 mice and autoimmune responses in mrl/lpr mice

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Background In trying to elucidate the value of new drug regimens in rheumatoid arthritis (RA), it is of critical importance to use animal models which share as many features as possible with the human disease. Collagen 0 induced arthritis) CIA) is characterised by development of both cellular and humoral immune responses directed against heterologous and autologous CII. Newly discovered diphenylpyrimidine amino acetamide derivatives pretreatment has been shown in vitro to reduce anti-CII antibody formation. Against this background, we wanted to investigate the clinical effects of SX-5452 on CIA and MRL/lpr. Objectives To investigate the effectiveness of SX-5452 in preventing the development of arthritis/autoimmune diseases and to compare the potency/mechanisms with Leflunomide, a novel anti-rheumatic drug. Methods Male DBA/1 mice and female MRL/lpr/lpr mice were used. The degrees of swelling, redness were evaluated macroscopically and intensity of inflammation was evaluated by histologically. At the same time the antibody formation was evaluated in vivo and in vitro. Results Oral administration of SX-5452(0.03 mg/kg/day-10 mg/kg/day) from the day of immunisation with CII strongly and dose-dependently suppressed the development of arthritis. SX-5452 at the dose of 10 mg/kg prevented completely the development of arthritis in both arthritic score and histological changes. Furthermore administration of SX-5452 at the dose of 10 mg/kg one a week also suppressed almost completely the development of CIA. It also showed inhibitory effect on the production of anti-CII antibody in CIA mice as well as anti-DNA antibody in MRL/lpr mice. These effects were at least three-fold more potent than those of leflunomide. MAPK-pathway and tyrosine phosphorylation are raised as the possible molecular mechanisms. Conclusion The development of CIA and autoimmune responses in MRL/lpr mice were markedly suppressed by SX-5452 via inhibition of anti-CII/anti-DNA antibodies formation. Since SX-5452 exerts no overt toxicity after repeated administration in mice, it is an interesting candidate for therapeutic use in rheumatoid arthritis.