Amide-based inhibitors of p38a 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 p38a 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)-a-methyl benzyl moiety were identified. These compounds exhibited improved cellular activities and maintained balance between p38a and CYP3A4 inhibition.