Drugs in Clinical Pipeline: PH-797804 | MAPK14 (p38 alpha) Kinase Inhibitor | Anti-inflammatory Drugs

PH-797804 [(aS)-3-{3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl}-N,4-dimethylbenzamde] is an oral, highly potent, selective and metabolically stable p38 mitogen-activated protein (MAP) kinase (MAPK14) inhibitor. In the kinase activity assay PH-797804 inhibits recombinant p38α kinase with an IC₅₀ value of 16 nM, showing 110-fold selectivity over p38β kinase (IC₅₀ value of 107 nM) [1, 2].

Structure of PH-797804 and its atropisomers 

Chemically, PH-797804 is diarylpyridinone scaffold bearing inhibitor of p38 mitogen-activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (aS). Computational studies first proposed the existence two atropisomers due to the steric bulk of the pyridinone carbonyl and the 6- and 6’-methyl substituents of racemic molecule. Chiral chromatography of racemate resolved into two atropisomers, PH-797804 (aS) and PH-797805 (aR).