Structure-based design, synthesis and biological evaluation of N-pyrazole, N′-thiazole urea inhibitors of MAP kinase p38α

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dc.contributor.authorGetlik M.
dc.contributor.authorGrutter C.
dc.contributor.authorSimard J.R.
dc.contributor.authorNguyen H.D.
dc.contributor.authorRobubi A.
dc.contributor.authorAust B.
dc.contributor.authorVan Otterlo W.A.L.
dc.contributor.authorRauh D.
dc.date.accessioned2012-02-22T09:27:07Z
dc.date.available2012-02-22T09:27:07Z
dc.date.issued2012
dc.description.abstractIn this paper, we present the structure-based design, synthesis and biological activity of N-pyrazole, N′-thiazole-ureas as potent inhibitors of p38α mitogen-activated protein kinase (p38α 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 p38α, resulting in potent type III inhibitors. [4-(3-tert-Butyl-5-{[(1,3-thiazol-2-ylamino)carbonyl]amino}-1H-pyrazol-1-yl) -phenyl]acetic acid 18c was found to be the most potent compound within this series and inhibited p38α 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)phenyl]acetate 18b, effectively inhibited p38α mediated phosphorylation of the mitogen activated protein kinase activated protein kinase 2 (MK2) in HeLa cells. © 2011 Elsevier Ltd. All rights reserved.
dc.identifier.citationEuropean Journal of Medicinal Chemistry
dc.identifier.citation48
dc.identifier.citation1
dc.identifier.citation15
dc.identifier.issn2235234
dc.identifier.otherdoi:10.1016/j.ejmech.2011.11.019
dc.identifier.urihttp://hdl.handle.net/10019.1/19826
dc.titleStructure-based design, synthesis and biological evaluation of N-pyrazole, N′-thiazole urea inhibitors of MAP kinase p38α
dc.typeArticle
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