Dibenzosuberones as p38 Mitogen-Activated Protein Kinase Inhibitors with Low ATP Competitiveness and Outstanding Whole Blood Activity

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• 作者：Stefan Fischer ; Heike K. Wentsch ; Svenja C. Mayer-Wrangowski ; Markus Zimmermann ; Silke M. Bauer ; Kirsten Storch ; Raimund Niess ; Solveigh C. Koeberle ; Christian Gr眉tter ; Frank M. Boeckler ; Daniel Rauh ; Stefan A. Laufer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：56
• 期：1
• 页码：241-253
• 全文大小：688K
• 年卷期：v.56,no.1(January 10, 2013)
• ISSN：1520-4804

文摘

p38伪 mitogen-activated protein (MAP) kinase is a main target in drug research concerning inflammatory diseases. Nevertheless, no inhibitor of p38伪 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 鈥渄eep pocket鈥?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.