Losmapimod

Losmapimod (GW856553,GW856553X,GSK-AHAB)是高效选择性p38 MAPK抑制剂,对p38α 和p38β的pKi值分别为8.1和7.6 [1].

p38 丝裂原活化蛋白激酶(p38 MAPK)是胞内信号激酶,在调节巨噬细胞和内皮细胞的炎症应答的转录和翻译中发挥重要作用[2].

Losmapimod是具有口服活性的p38 MAPK抑制剂.在盐-脂肪饮食的自发性高血压卒中倾向大鼠(SHR-SPs)中,GSK-AHAB以剂量依赖的方式显著促进存活和肾功能,并诱导血管舒张.GSK-AHAB也能降低高血压\心脏重塑\血脂异常\血浆肾素活性(PRA)\白介素-1(IL-1)和醛固酮[1].在高胆固醇血症病人中,Losmapimod能将乙酰胆碱\硝普化钠和NG-monomethyl-L-arginine (L-NMMA)应答分别提高25%\20%和10%.Losmapimod也能将C-反应蛋白(一种全身性炎症标志物)降低57%.这些结果表明,Losmapimod促进NO介导的血管舒张,抑制炎症[2].在慢性阻塞性肺病(COPD)病人中,Losmapimod(7.5 mg每天两次)降低17%的血浆纤维蛋白原,并具有良好的耐受性[3].

参考文献：
[1].  Willette RN, Eybye ME, Olzinski AR, et al. Differential effects of p38 mitogen-activated protein kinase and cyclooxygenase 2 inhibitors in a model of cardiovascular disease. J Pharmacol Exp Ther, 2009, 330(3): 964-970.
[2].  Cheriyan J, Webb AJ, Sarov-Blat L, et al. Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. Circulation., 2011, 123(5): 515-523.
[3].  Lomas DA, Lipson DA, Miller BE, et al. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J Clin Pharmacol, 2012, 52(3): 416-424.