| 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.
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