Amide-based inhibitors of p38α MAP kinase. Part 1: Discovery of novel N-pyridyl amide lead molecules

A novel series of N-pyridyl amides as potent p38α kinase inhibitors is described. Based on the structural similarities between the initial hit and a well-known imidazole pyrimidine series of p38α inhibitors, potencies within the newly discovered series were quickly improved by installation of an (S)-α-methylbenzyl moiety at the 2-position of the pyridine ring. The proposed binding modes of the new series to p38α were evaluated against SAR findings and provided rationale for further development of this series of molecules.

Graphical abstractA novel series of N-pyridyl amide p38α kinase inhibitors is described. The proposed binding modes of the initial hits were evaluated against SAR findings to provide rationale for further development of this structural class.Figure optionsDownload full-size imageDownload as PowerPoint slide