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

In this paper, we present the structure-based design, synthesis and biological activity of N-pyrazole, N'thiazole-ureas as potent inhibitors of p38 alpha mitogen-activated protein kinase (p38 alpha 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 p38 alpha, 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 p38 alpha activity with an IC50 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 p38 alpha mediated phosphorylation of the mitogen activated protein kinase activated protein kinase 2 (MK2) in HeLa cells. (C) 2011 Elsevier Masson SAS. All rights reserved.