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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
chemistry
Structure-based design, synthesis and biological evaluation of N-pyrazole, N′-thiazole urea inhibitors of MAP kinase p38α
European Journal of Medicinal Chemistry, Volume 48, Year 2012
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Description
In 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.
Authors & Co-Authors
Getlik, Matthäus
Germany, Dortmund
Chemical Genomics Centre of the Max Planck Society
Grütter, Christian
Germany, Dortmund
Chemical Genomics Centre of the Max Planck Society
Germany, Dortmund
Technische Universität Dortmund
Simard, Jeffrey R.
Germany, Dortmund
Chemical Genomics Centre of the Max Planck Society
Nguyen, Hoang D.
Germany, Dortmund
Chemical Genomics Centre of the Max Planck Society
Robubi, Armin
Germany, Dortmund
Chemical Genomics Centre of the Max Planck Society
Aust, Beate
Germany, Dortmund
Chemical Genomics Centre of the Max Planck Society
van Otterlo, Willem A. L.
South Africa, Johannesburg
University of the Witwatersrand
South Africa, Stellenbosch
Stellenbosch University
Rauh, Daniel F.
Germany, Dortmund
Chemical Genomics Centre of the Max Planck Society
Germany, Dortmund
Technische Universität Dortmund
Statistics
Citations: 25
Authors: 8
Affiliations: 4
Identifiers
Doi:
10.1016/j.ejmech.2011.11.019
ISSN:
02235234
e-ISSN:
17683254