Dibenzosuberones as p38 Mitogen-Activated Protein Kinase Inhibitors with Low ATP Competitiveness and Outstanding Whole Blood Activity
Dibenzosuberones as p38 Mitogen-Activated Protein Kinase Inhibitors with Low ATP Competitiveness and Outstanding Whole Blood Activity
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DOI：
10.1021/jm301539x
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发表时间：
2013-01-10
影响因子：
7.3
通讯作者：
Laufer, Stefan A.
中科院分区：
文献类型：
--
作者：
Fischer, Stefan;Wentsch, Heike K.;Laufer, Stefan A.
p38 α丝裂原活化蛋白（MAP）激酶是炎症性疾病药物研究的主要靶点。然而，没有p38 α MAP激酶的抑制剂被引入市场。这可能是由于没有抑制剂在生物系统中具有突出的活性和选择性。本文描述了一种基于高选择性分子探针Skepinone-L开发此类抑制剂的方法。引入寻址DFG基序的“深口袋”部分导致化合物的活性增加。亲水部分位于邻近亲水区域II的溶剂暴露区域，在全血测定中保留了化合物的高活性。结合其出色的选择性和低ATP竞争性，这些抑制剂是用于生物系统和治疗的非常有趣的候选者。
p38 alpha mitogen-activated protein (MAP) kinase is a main target in drug research concerning inflammatory diseases. Nevertheless, no inhibitor of p38 alpha MAP kinase has been introduced to the market. This might be attributed to the fact that there is no inhibitor which combines outstanding activity in biological systems and selectivity. Herein an approach to the development of such inhibitors on the basis of the highly selective molecular probe Skepinone-L is described. Introduction of a "deep pocket" moiety addressing the DFG motif led to an increased activity of the compounds. Hydrophilic moieties, addressing the solvent-exposed area adjacent to hydrophilic region II, conserved a high activity of the compounds in a whole blood assay. Combined with their outstanding selectivity and low ATP competitiveness, these inhibitors are very interesting candidates for use in biological systems and in therapy.