Background:

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 clinical trials for the treatment of inflammatory diseases. In stable atherosclerosis, treatment with BMS-582949 for 12 weeks did not reduce arterial inflammation or hs-CRP compared to placebo whereas intensification of statin therapy significantly decreased arterial inflammation [2].

参考文献:
[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.