A new structural class of triaminotriazine aniline amides possessing potent p38 enzyme activityhas been discovered. The initial hit (compound 1a) was identified through screening thePharmacopeia ECLiPS compound collection. SAR modification led to the identification of ashort acting triaminotriazine aniline methoxyamide (compound 1m) possessing in vitro andin vivo oral activity in animal models of acute and chronic inflammatory disease. An X-raycrystal structure of compound 1m in this class, cocrystallized with unactivated p38α protein,indicates that these compounds bind to the ATP binding pocket and possess key H-bondinginteractions within a deeper cleft. Hydrogen bonding between one of the triazine nitrogensand the backbone NH of the Met109 residue occurs through a water molecule. The methoxyamide NH and carbonyl oxygen are within H-bonding distance of Glu71 and Asp168.
