Dibenzosuberones as p38 mitogen-activated protein kinase inhibitors with low ATP competitiveness and outstanding whole blood activity.

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Fischer S, Wentsch HK, Mayer-Wrangowski SC, Zimmermann M, Bauer SM, Storch K, Niess R, Koeberle SC, Grutter C, Boeckler FM, Rauh D, Laufer SA

Dibenzosuberones as p38 mitogen-activated protein kinase inhibitors with low ATP competitiveness and outstanding whole blood activity.

J Med Chem. 2013 Jan 10;56(1):241-53. doi: 10.1021/jm301539x. Epub 2012 Dec 27.

PubMed ID

23270382 [ View in PubMed

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Abstract

p38alpha mitogen-activated protein (MAP) kinase is a main target in drug research concerning inflammatory diseases. Nevertheless, no inhibitor of p38alpha 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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Doramapimod	Mitogen-activated protein kinase 14	Kd (nM)	12	N/A	N/A	Details