3,4-Diaryl-isoxazoles and -imidazoles as Potent Dual Inhibitors of p38α Mitogen Activated Protein Kinase and Casein Kinase 1δ

In this study, we report on the discovery of isoxazole 1 as a potent dual inhibitor of p38 alpha (IC50=0.45 mu M) and CK1 delta (IC50=0.23 mu M). Because only it few effective small molecule inhibitors of CK1 have been described so far, we aimed to develop this structural class toward specific agents. Molecular modeling studies comparing p38 alpha/CK1 delta suggested an optimization strategy leading to design, synthesis, biological characterization, and SAR of highly potent compounds including 9 (IC50 p38 alpha=0.006 mu M; IC50 CK1 delta=1.6 mu M), 13(IC50 p38 alpha=2.52 mu M; IC(50)CK1 delta=0.033 mu M), 17(IC50 p38 alpha=0.019 mu M; IC50 CK1 delta=0.004 mu M; IC50 CK1 epsilon=0.073 mu M), and 18 (CKP138) (IC50 p38 alpha=0.041 mu M; IC50 CK1 delta=0.005 mu M; IC50 CK1 epsilon=0.447 mu M) possessing differentiated specificity. Selected compounds were profiled over 76 kinases and evaluation of their cellular efficacy showed 18(CKP138) to be a highly potent and dual-specific inhibitor of CK1 delta and p38 alpha.