Biological Activity
bms-582949 hydrochloride is a novel, potent and highly selective p38α mitogen-activated protein kinase (p38α mapk) inhibitor [1].the p38α map kinase plays a critical role in regulating the production of many inflammatory cytokines, including tnf-α and il-1β. excessive production of tnf-α and il-1β has been implicated in many inflammatory diseases [1].bms-582949 hydrochloride potently inhibited the activity of p38α mapk with the ic50 value of 13 nm [1]. bms-582949 showed no significant effects on cytochrome p450 isozymes 1a2, 2c9, 2c19, and 2d6 with the ic50 values of >40 μm. bms-582949 weakly inhibited the activity of cyp3a4, with the ic50 value of 18-40 μm. bms-582949 displayed >2000-fold selectivity for p38α over a diverse panel of 57 kinases, include serine kinases, receptor tyrosine kinases, nonreceptor tyrosine kinases, and the p38γ and δ isoforms. bms-582949 showed 450-fold selectivity over jnk2, a map kinase involved in inflammation, and 190-fold selective over raf [1]. in mice, after oral administration of bms-582949 (10 mg/kg), the clearance rate for bms-582949 is 4.4 ml/min/kg. bms-582949 exhibited oral bioavailability values of 90% and 60% in mice and rats, respectively [1].bms-582949 is currently under phase ii
References
[1] liu c, lin j, wrobleski s t, 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]. journal of medicinal chemistry, 2010, 53(18): 6629-6639.
[2] emami h, vucic e, subramanian s, et al. the effect of bms-582949, a p38 mitogen-activated protein kinase (p38 mapk) inhibitor on arterial inflammation: a multicenter fdg-pet trial[j]. atherosclerosis, 2015, 240(2): 490-496.
