Discovery and Characterization of Atropisomer PH‐797804, a p38 MAP Kinase Inhibitor, as a Clinical Drug Candidate

Abstract PH‐797804 ((a S )‐3‐{3‐bromo‐4‐[(2,4‐difluorobenzyl)oxy]‐6‐methyl‐2‐oxopyridin‐1(2 H )‐yl}‐ N ,4‐dimethylbenzamde) is a diarylpyridinone inhibitor of p38 mitogen‐activated protein (MAP) kinase derived from a racemic mixture as the more potent atropisomer (a S ), first proposed by molecular modeling and subsequently confirmed by experiments. Due to steric constraints imposed by the pyridinone carbonyl group and the 6‐ and 6′‐methyl substituents of PH‐797804, rotation around the connecting bond of the pyridinone and the N ‐phenyl ring is restricted. Density functional theory predicts a remarkably high rotational energy barrier of >30 kcal mol −1 , corresponding to a half‐life of more than one hundred years at room temperature. This gives rise to discrete conformational spaces for the N ‐phenylpyridinone group, and as a result, two atropic isomers that do not interconvert under ambient conditions. Molecular modeling studies predict that the two isomers should differ in their binding affinity for p38α kinase; whereas the atropic S (a S ) isomer binds favorably, the opposite a R isomer incurs significant steric interference with p38α kinase. The two isomers were subsequently identified and separated by chiral chromatography. IC 50 values from p38α kinase assays confirm that one atropisomer is >100‐fold more potent than the other. It was ultimately confirmed by small‐molecule X‐ray diffraction that the more potent atropisomer, PH‐797804, is the a S isomer of the racemic pair. Extensive pharmacological characterization supports that PH‐797804 carries most activity both in vitro and in vivo, and it has a stability profile compatible with oral formulation and delivery options.