BMS-582949 was identified as a highly selective p38α MAP kinase inhibitor as early in 2010.
Moreover, it has entered into clinical trials for further development and clinical studies in inflammatory disease.
The identification and development of inhibitors of p38 MAPK as orally active therapeutic agents to treat inflammatory diseases has been one of the most active research areas in drug discovery. Because p38α MAPK plays a critical role in regulating the biosynthesis of many inflammatory cytokines. Tumor necrosis TNF-α and IL-1β represents two main cytokines. P38α inhibitor represents a promising solution for the treatment of inflammatory diseases.
For instance, blockage of TNF-α function by such as Etanercept, a soluble TNF-α receptor, and Infliximab, a TNF-α antibody, has proven effective in rheumatoid arthritis and other autoimmune diseases.
Besides, BMS 582949 displayed a p38α IC50 of 13 nM and a cellular TNFα IC50 of 50 nM. Additionally, in this study, compounds were administrated to mice prior to challenging with LPS. in addition, BMS 582949 is active and reduces TNFα production by 78%. It also displayed dose-dependent reduction in paw swelling with qd dosing, with efficacy observed at doses of 10 and 100 mg/kg. Furthermore, with bid dosing, BMS 582949 showed improved efficacy, achieving marked reduction in paw swelling at doses of 1 and 5 mg/kg.
Another study from Hamed Emami in 2015 evaluated the effect of BMS-582949, on atherosclerotic plaque inflammation, using 18FDG-PET imaging in clinical trials.
To sum up, in the near future, BMS 582949 could be an effective drug for inflammatory diseases treatment.
1. Liu C, et al. Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo[1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases. J Med Chem. 2010 Sep 23;53(18):6629-39.