Novel heterocycle-substituted pyrimidines as inhibitors of NF-kappaB transcription regulation related to TNF-alpha cytokine release.

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