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Beschreibung

A cell-permeable pyridylsulfone that acts as a selective, high affinity PPARbeta (PPARdelta) ligand (IC50 in PPAR ligand displacement assays = 200 nM against human PPARbeta and >10 µ,M against PPARalpha or PPARgamma) and effectively antagonizes agonist-induced, but not basal, PPARbeta transcription activity both in cultures in vitro (IC50 = 126 nM in CV-1 cells) and in mice in vivo (82% and 71% inhibition of 10 mg/kg GW0742-induced Adrp and Angptl4 mRNA upregulation, respectively, in colon epithelium, 10 mg/kg GSK3787, p.o.) by covalently modifying PPARbeta at Cys249. GSK3787 is also shown to exhibit weak agonistic activity toward PPARgamma (1.2-fold increase above basal level by 1 µ,M GSK3787), and effectively block the more potent agonist GW1929 (Cat. Nos. 370695) from further stimulation (1.5 and 3.5-fold above basal by 0.3 µ,M GW1929 in the presence or absence of 1 µ,M GSK3787, respectively)., A cell-permeable and orally available pyridylsulfone compound that acts as a selective, high affinity PPARbeta (PPARdelta) ligand (IC50 in PPAR ligand displacement assays = 200 nM against human PPARbeta and >10 µ,M against PPARalpha or PPARgamma) and effectively antagonizes agonist-induced, but not basal, PPARbeta transcription activity both in cultures in vitro (IC50 = 126 nM against 2 nM GW501516-induced reporter transcription in CV-1 cells) and in mice in vivo (82% and 71% inhibition of 10 mg/kg GW0742-induced Adrp and Angptl4 mRNA upregulation, respectively, in colon epithelium by 10 mg/kg GSK3787, p.o.) by covalently modifying PPARbeta at Cys249. GSK3787 is also shown to exhibit weak agonistic activity toward PPARgamma (1.2-fold increase above basal level by 1 µ,M GSK3787), and effectively block the more potent agonist GW1929 (Cat. Nos. 370695) from further stimulation (1.5 and 3.5-fold above basal by 0.3 µ,M GW1929 in the presence or absence of 1 µ,M GSK3787, respectively).