Target Engagement Analysis and Link to Pharmacodynamic Endpoint for a Novel Class of CNS-penetrant and Efficacious p38α MAPK Inhibitors
Target Engagement Analysis and Link to Pharmacodynamic Endpoint for a Novel Class of CNS-penetrant and Efficacious p38α MAPK Inhibitors
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DOI：
10.1007/s11481-014-9543-3
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发表时间：
2014-09-01
影响因子：
6.2
通讯作者：
Van Eldik, Linda J.
中科院分区：
文献类型：
--
作者：
Bachstetter, Adam D.;Watterson, D. Martin;Van Eldik, Linda J.
蛋白激酶，p38αMAPK，是应激源诱导的神经炎性反应的关键细胞内转导，因此，作为潜在的治疗靶点具有很高的兴趣。我们最近报道了一流的中枢神经系统穿透性和高度特异性的p38 MAPK抑制剂的合成和评价，它们避免了数百份先前报告中使用的流行的小分子p38 MAPK抑制剂中出现的靶向交叉问题。以MW181为代表的新型p38MAPK抑制剂在体内是有效的。药效学作用包括减轻应激源诱导的脑促炎细胞因子水平的增加。我们在这里报告了对MW181靶点参与以及与下游胶质细胞促炎细胞因子产生增加的特异性联系的更详细的分析。体内验证包括证明口服MW181可以抑制脂多糖诱导的小鼠脑内IL-1β、TNFα、IL-6、IL-10和CXCL1的增加，但不能抑制耐药的p38αMAPK突变小鼠的增加。
The protein kinase, p38 alpha MAPK, is a key intracellular transducer of stressor-induced neuroinflammatory responses and, as such, is of high interest as a potential therapeutic target. We recently reported the synthesis and evaluation of first-in-class CNS-penetrant and highly specific p38 MAPK inhibitors that avoid target crossover issues seen in popular small molecule p38 MAPK inhibitors used in hundreds of previous reports. The novel p38 MAPK inhibitors, represented in this study by MW181, are efficacious in vivo. Pharmacodynamic actions include attenuation of stressor-induced increases in brain proinflammatory cytokine levels. We report here more detailed analyses of MW181 target engagement and specific linkage to the downstream increase in glia proinflammatory cytokine production. In vivo validation included demonstration that oral administration of MW181 suppresses lipopolysaccharide-induced increases in mouse brain IL-1 beta, TNF alpha, IL-6, IL-10, and CXCL1 but not in a drug-resistant p38 alpha MAPK mutant mouse.