| Biological Description |
INT-767 is a potent agonist for both FXR (mean EC50, 30 nM) and TGR5 (mean EC50, 630 nM by time resolved-fluorescence resonance energy transfer).
IC50 value: 30 nM (EC50, FXR), 630 nM (EC50, TGR5)[2]
Target: FXR/TGR5
in vitro: INT-767 is the first compound described so far to potently and selectively activate both BA receptors. INT-767 significantly induces bile flow and biliary HCO3- output, as well as gene expression of carbonic anhy-drase 14, an important enzyme able to enhance HCO3- transport, in an Fxr-dependent manner[1]. INT-767 induces FXR-dependent lipid uptake by adipocytes, with the beneficial effect of shuttling lipids from central hepatic to peripheral fat storage, and promotes TGR5-dependent glucagon-like peptide-1 secretion by enteroendocrine cells, a validated target in the treatment of type 2 diabetes. INT-767 is a safe and effective modulator of FXR and TGR5-dependent pathways, suggesting potential clinical applications in the treatment of liver and metabolic diseases[2].
in vivo: INT-767 is a novel promising treatment in a mouse model of chronic cholangiopathy and characterized the underlying molecular and cellular mechanisms. INT-767 significantly improves serum liver enzymes, hepatic inflammation, and biliary fibrosis in Mdr2-/-mice. INT-767 dramatically reduces bile acid synthesis via the induction of ileal Fgf15 and hepatic Shpgene expression, thus resulting in significantly reduced biliary bile acid output in Mdr2-/- mice[1]. Moreover, INT-767 treatment markedly decreases cholesterol and triglyceride levels in diabetic db/db mice and in mice rendered diabetic by streptozotocin administration[2]. |
