Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist.

Abstract

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 6α-ethyl-3α,7α-dihydroxy-5β-cholan-24-oic acid (INT-747), a potent and selective FXR agonist, as well as 6α-ethyl-23(S)-methyl-3α,7α,12α-trihydroxy-5β-cholan-24-oic acid (INT-777), a potent and selective TGR5 agonist. Here we characterize 6α-ethyl-3α,7α,23-trihydroxy-24-nor-5β-cholan-23-sulfate sodium salt (INT-767), a novel semisynthetic 23-sulfate derivative of INT-747. INT-767 is a potent agonist for both FXR (mean EC(50), 30 nM by PerkinElmer AlphaScreen assay) and TGR5 (mean EC(50), 630 nM by time resolved-fluorescence resonance energy transfer), the first compound described so far 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 ether-a-go-go-related gene 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 glucagon-like peptide-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.

• Authors: Giovanni Rizzo, Daniela Passeri, Francesca De Franco, Gianmario Ciaccioli, Loredana Donadio, Giorgia Rizzo, Stefano Orlandi, Bahman Sadeghpour, Xiaoxin X Wang, Tao Jiang, Moshe Levi, Mark Pruzanski, Luciano Adorini
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 78 Issue 4 Pg. 617-30 (Oct 2010) ISSN: 1521-0111 [Electronic] United States
• PMID: 20631053 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• 6-ethyl-24-norcholane-3,7,23-triol-23 sulfate
• Bile Acids and Salts
• GPBAR1 protein, human
• Receptors, Cytoplasmic and Nuclear
• Receptors, G-Protein-Coupled
• farnesoid X-activated receptor

Topics

• Animals
• Bile Acids and Salts (chemical synthesis, metabolism, pharmacology)
• CHO Cells
• Cricetinae
• Cricetulus
• Hep G2 Cells
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Obese
• NIH 3T3 Cells
• Receptors, Cytoplasmic and Nuclear (agonists, physiology)
• Receptors, G-Protein-Coupled (agonists, physiology)