Ligand-protein interactions of selective casein kinase 1δ inhibitors.

Casein kinase 1 delta (CK1 delta) and 1 epsilon (CK1 epsilon) are believed to be necessary enzymes for the regulation of circadian rhythms in all mammals. On the basis of our previously published work demonstrating a CK1 epsilon-preferring compound to be an ineffective circadian clock modulator, we have synthesized a series of pyrazole-substitued pyridine inhibitors, selective for the CK1 delta isoform. Additionally, using structure-based drug design, we have been able to exploit differences in the hinge region between CK1 delta and p38 to find selective inhibitors that have minimal p38 activity. The SAR, brain exposure, and the effect of these inhibitors on mouse circadian rhythms are described. The in vivo evaluation of these inhibitors demonstrates that selective inhibition of CK1 delta at sufficient central exposure levels is capable of modulating circadian rhythms.