3,4-Diaryl-isoxazoles and -imidazoles as potent dual inhibitors of p38α mitogen activated protein kinase and casein kinase 1δ

Abstract

In this study, we report on the discovery of isoxazole 1 as a potent dual inhibitor of p38α (IC50 = 0.45 μM) and CK1δ (IC 50 = 0.23 μM). Because only a 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 p38α/CK1δ suggested an optimization strategy leading to design, synthesis, biological characterization, and SAR of highly potent compounds including 9 (IC50 p38α = 0.006 μM; IC50 CK1δ = 1.6 μM), 13 (IC50 p38α = 2.52 μM; IC 50 CK1δ = 0.033 μM), 17 (IC50 p38α = 0.019 μM; IC50 CK1δ = 0.004 μM; IC50 CK1ε = 0.073 μM), and 18 (CKP138) (IC50 p38α = 0.041 μM; IC 50 CK1δ = 0.005 μM; IC50 CK1ε = 0.447 μM) 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 CK1δ and p38α. ©2009 American Chemical Society.