Novel heterocycle-substituted pyrimidines as inhibitors of NF-κB transcription regulation related to TNF-α cytokine release

Novel heterocyclic ring-substituted pyrimidines have been designed as inhibitors of glycogen synthase kinase-3β (GSK-3β) from the modification of known inhibitors. Several potent inhibitors exhibiting nanomolar activities were discovered against GSK-3β kinase as well as in an NF-κB reporter gene assay. Based on the results from in vitro TNF-α release inhibition and in vivo endotoxima, these inhibitors are expected to be useful candidates for treatment of inflammation-related diseases.

Graphical abstractNovel heterocyclic ring-substituted pyridines have been designed as inhibitors of glycogen synthase kinase-3β and compound 22 exhibited good GSK-3β and NF-κB inhibition as well as desirable cellular activity.Figure optionsDownload full-size imageDownload as PowerPoint slide