T-5224

T-5224 is a small molecule inhibitor of c-Fos/AP-1 that specifically inhibits the binding of AP-1 to the AP-1 binding site of the promoter region, attenuates the gelatinase activity of MMP-2 and -9; inhibits the mRNA expression levels of MMP-1, 3, and 13, and IL-1β, TNF-α and IL-6 in IL-1-stimulated human chondrocytes, significantly inhibits the invasion, migration, and MMP activity of HNSCC cells, prevents lymph node metastasis in an oral cancer model; decreases the release of collagen selectively in SSc fibroblasts, prevents dermal fibrosis in vivo.Rheumatoid Arthritis Phase 2 Discontinued(In Vitro):T-5224 inhibits in-vitro production of the mediators MMP-1, MMP-3, IL-6 and TNF-α by IL-1β-stimulated human synovial SW982 cells with the mean IC50 of about 10 μM.T-5224 (0-80 μM) significantly inhibits the invasion, migration, and MMP activity of HSC-3-M3 cells in a dose-dependent manner.(In Vivo):Administration of T-5224 (300 mg/kg, p.o.) after intraperitoneal injection of LPS impartes appreciable protection against acute elevations in serum levels of TNFα, HMGB1, ALT/AST as well as in liver tissue levels of MIP-1α and MCP-1, and reduces the lethality (27%).G2 is observed in rat and monkey liver microsomes as a major metabolite of T-5224, suggesting that G2 is not a human-specific metabolite.T-5224 (300 mg/kg, p.o.) inhibits the production of TNF-alpha and other downstream effectors in C57BL/6 mice.