Amide-based inhibitors of p38alpha MAP kinase. Part 1: discovery of novel N-pyridyl amide lead molecules.

A novel series of N-pyridyl amides as potent p38alpha kinase inhibitors is described. Based on the structural similarities between the initial hit and a well-known imidazole pyrimidine series of p38alpha inhibitors, potencies within the newly discovered series were quickly improved by installation of an (S)-alpha-methylbenzyl moiety at the 2-position of the pyridine ring. The proposed binding modes of the new series to p38alpha were evaluated against SAR findings and provided rationale for further development of this series of molecules.

Amide-based inhibitors of p38alpha MAP kinase. Part 2: design, synthesis and SAR of potent N-pyrimidyl amides.

Optimization of a tri-substituted N-pyridyl amide led to the discovery of a new class of potent N-pyrimidyl amide based p38alpha MAP kinase inhibitors. Initial SAR studies led to the identification of 5-dihydrofuran as an optimal hydrophobic group. Additional side chain modifications resulted in the introduction of hydrogen bond interactions. Through extensive SAR studies, analogs bearing free amino groups and alternatives to the parent (S)-alpha-methyl benzyl moiety were identified. These compounds exhibited improved cellular activities and maintained balance between p38alpha and CYP3A4 inhibition.