Structure-based design, synthesis and biological evaluation of N-pyrazole, N'-thiazole urea inhibitors of MAP kinase p38alpha.

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Getlik M, Grutter C, Simard JR, Nguyen HD, Robubi A, Aust B, van Otterlo WA, Rauh D

Structure-based design, synthesis and biological evaluation of N-pyrazole, N'-thiazole urea inhibitors of MAP kinase p38alpha.

Eur J Med Chem. 2012 Feb;48:1-15. doi: 10.1016/j.ejmech.2011.11.019. Epub 2011 Nov 18.

PubMed ID

22154891 [ View in PubMed

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Abstract

In this paper, we present the structure-based design, synthesis and biological activity of N-pyrazole, N'-thiazole-ureas as potent inhibitors of p38alpha mitogen-activated protein kinase (p38alpha MAPK). Guided by complex crystal structures, we employed the initially identified N-aryl, N'-thiazole urea scaffold and introduced key structural elements that allowed the formation of novel hydrogen bonding interactions within the allosteric site of p38alpha, resulting in potent type III inhibitors. [4-(3-tert-Butyl-5-{[(1,3-thiazol-2-ylamino)carbonyl]amino}-1H-pyrazol-1-yl)-phen yl]acetic acid 18c was found to be the most potent compound within this series and inhibited p38alpha activity with an IC(50) of 135 +/- 21 nM. Its closest analog, ethyl [4-(3-tert-butyl-5-{[(1,3-thiazol-2-ylamino)carbonyl]amino}-1H-pyrazol-1-yl)pheny l]acetate 18b, effectively inhibited p38alpha mediated phosphorylation of the mitogen activated protein kinase activated protein kinase 2 (MK2) in HeLa cells.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Doramapimod	Mitogen-activated protein kinase 14	Kd (nM)	7.5	N/A	N/A	Details
Doramapimod	Mitogen-activated protein kinase 14	IC 50 (nM)	8	N/A	N/A	Details