Functional characterization of the semisynthetic bile acid derivative INT-767, a
dual farnesoid X receptor and TGR5 agonist.
Authors Rizzo G, Passeri D, De Franco F, Ciaccioli G, Donadio L, Rizzo G, Orlandi S,
Sadeghpour B, Wang XX, Jiang T, Levi M, Pruzanski M, Adorini L
Submitted By Moshe Levi on 7/31/2010
Status Published
Journal Molecular pharmacology
Year 2010
Date Published 10/1/2010
Volume : Pages 78 : 617 - 630
PubMed Reference 20631053
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
6a-ethyl-3a,7a-dihydroxy-5ß-cholan-24-oic acid (INT-747), a potent and selective
FXR agonist, as well as
6a-ethyl-23(S)-methyl-3a,7a,12a-trihydroxy-5ß-cholan-24-oic acid (INT-777), a
potent and selective TGR5 agonist. Here we characterize
6a-ethyl-3a,7a,23-trihydroxy-24-nor-5ß-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.

Investigators with authorship
Moshe LeviGeorgetown University