RT Journal Article SR Electronic T1 Functional characterization of the semi-synthetic bile acid derivative INT-767, a dual FXR and TGR5 agonist JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP mol.110.064501 DO 10.1124/mol.110.064501 A1 Giovanni Rizzo A1 Daniela Passeri A1 Francesca De Franco A1 Gianmario Ciaccioli A1 Loredana Donadio A1 Giorgia Rizzo A1 Stefano Orlandi A1 Bahman Sadeghpour A1 Xiaoxin Wang A1 Tao Jiang A1 Moshe Levi A1 Mark Pruzanski A1 Luciano Adorini YR 2010 UL http://molpharm.aspetjournals.org/content/early/2010/07/14/mol.110.064501.abstract AB Two dedicated receptors for bile acids (BAs) have been identified, the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, which represent attractive targets for the treatment of metabolic and chronic liver diseases. Previous work characterized INT-747, a 6α-ethyl derivative of chenodeoxycholic acid (CDCA) and a potent and selective FXR agonist, as well as INT-777, a 6α-ethyl-23(S)-methyl derivative of cholic acid (CA) and a potent and selective TGR5 agonist. Here we characterize INT-767, a novel semi-synthetic 23-sulfate derivative of INT-747. INT-767 is a potent agonist for both FXR (mean EC50 30 nM by alphascreen assay) and TGR5 (mean EC50 630 nM by TR-FRET), the first compound so far described to potently and selectively activate both BA receptors. INT-767 does not show cytotoxic effects in HepG2 cells, does not inhibit cytochrome P450 enzymes, is highly stable to phase I and II enzymatic modifications, and does not inhibit the human ERG potassium channel. In line with its dual activity, 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 GLP-1 secretion by enteroendocrine cells, a validated target in the treatment of type 2 diabetes. Moreover, INT-767 treatment markedly decreases cholesterol and triglyceride levels in diabetic db/db mice and in mice rendered diabetic by streptozotocin administration. Collectively, these preclinical results indicate that 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.