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.
Department of Chemistry, Seoul National University, Seoul 151-747, Republic of Korea.
Hyung-Ho
HH
Ha
Jee Seon
JS
Kim
B Moon
BM
Kim
D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D016328:NF-kappa B; D011743:Pyrimidines; D014409:Tumor Necrosis Factor-alpha; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3