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 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 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 p38α mediated phosphorylation of the mitogen activated protein kinase activated protein kinase 2 (MK2) in HeLa cells.

The SAR of a series of N-pyrazole, N′-thiazole-ureas was explored systematically and resulted in ethyl [4-(3-tert-butyl-5-{[(1,3-thiazol-2-ylamino)carbonyl]amino}-1H-pyrazol-1-yl)phenyl]acetate (18b) with potent cellular activity against p38α. Figure optionsDownload as PowerPoint slideHighlights
► FLiK assay technology to identify stabilizers of enzymatically inactive p38α.
► Protein X-ray crystallography of screening hits.
► Novel binding mode of screening hit.
► Structure-based design approaches to improve inhibitor potency.