Design and synthesis of novel p38alpha MAP kinase inhibitors: discovery of pyrazole-benzyl ureas bearing 2-molpholinopyrimidine moiety.

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Arai T, Ohno M, Inoue H, Hayashi S, Aoki T, Hirokawa H, Meguro H, Koga Y, Oshida K, Kainoh M, Suyama K, Kawai H

Design and synthesis of novel p38alpha MAP kinase inhibitors: discovery of pyrazole-benzyl ureas bearing 2-molpholinopyrimidine moiety.

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

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22749282 [ View in PubMed

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Abstract

The discovery that pyrazole-benzyl urea derivatives bearing a 2-molpholinopyrimidine moiety are novel p38alpha 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 p38alpha 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Doramapimod	Mitogen-activated protein kinase 14	IC 50 (nM)	10	N/A	N/A	Details