Amide-based inhibitors of p38a MAP kinase. Part 1: Discovery of novel N-pyridyl amide lead molecules

A novel series of N-pyridyl amides as potent p38a kinase inhibitors is described. Based on the structural similarities between the initial hit and a well-known imidazole pyrimidine series of p38a inhibitors, potencies within the newly discovered series were quickly improved by installation of an (S)-a-methylbenzyl moiety at the 2-position of the pyridine ring. The proposed binding modes of the new series to p38a were evaluated against SAR findings and provided rationale for further development of this series of molecules.