Institute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen , Auf der Morgenstelle 8, 72076 Tübingen, Germany.
J Med Chem. 2012 Sep 13;55(17):7862-74. doi: 10.1021/jm300951u. Epub 2012 Aug 29.
The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38α MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the "deep pocket", and the hinge glycine flip of the kinase. Potent inhibitors with IC(50) values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the "deep pocket" in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography.
p38 MAP 激酶是调节炎症细胞因子生物合成的信号通路中的关键因子。小分子 p38 抑制剂抑制这些细胞因子的产生。因此，p38 是新型抗炎药物的一个很有前途的药物靶点。在这项研究中，我们报告了新型二苯并[e,g]喹嗪酮、二苯并[b,f]氧杂卓和苯并[h]色烯酮作为 p38α MAP 激酶抑制剂。先前报道的二苯并[e,g]喹嗪酮和二苯并[b,f]氧杂卓通过引入官能团或去除一个苯基环进行了化学修饰。这应该导致靶向激酶的疏水区 I、“深口袋”和 hinge 甘氨酸翻转。确定了具有 IC50 值在个位数纳摩尔范围内（高达 3 nM）的有效抑制剂。通过蛋白质 X 射线晶体学观察到，与 DFG-out 构象中的“深口袋”不同，与 DFG 基序的相互作用可以在 in-conformation 中观察到。
