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Bioorg Med Chem Lett. 2012 Aug 1;22(15):5118-22. doi: 10.1016/j.bmcl.2012.05.095. Epub 2012 Jun 12.

Design and synthesis of novel p38α MAP kinase inhibitors: discovery of pyrazole-benzyl ureas bearing 2-molpholinopyrimidine moiety.

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Pharmaceutical Research Laboratories, Toray Industries, Inc., Kamakura, Kanagawa, Japan.


The discovery that pyrazole-benzyl urea derivatives bearing a 2-molpholinopyrimidine moiety are novel p38α inhibitors is described. A comparative view of the binding modes of SB-203580 and BIRB-796 by structural alignment of two X-ray co-crystal structures was utilized to identify this novel series. Modification of the benzyl group led to compound 2b, a highly potent p38α inhibitor. In in vivo studies, 2b inhibited the production of tumor necrosis factor-alpha in lipopolysaccharide-treated mouse in a dose-dependent manner. Furthermore, the results of a 5-day repeated oral dose toxicity study suggest that 2b has low hepatotoxicity.

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