Functional Characterization of the Semisynthetic Bile Acid Derivative INT-767, a Dual Farnesoid X Receptor and TGR5 Agonist

被引：151

作者：

Rizzo, Giovanni ^{[1
]}

Passeri, Daniela ^{[1
]}

De Franco, Francesca ^{[1
]}

Ciaccioli, Gianmario ^{[1
]}

Donadio, Loredana ^{[1
]}

Rizzo, Giorgia ^{[1
]}

Orlandi, Stefano ^{[1
]}

Sadeghpour, Bahman ^{[1
]}

Wang, Xiaoxin X. ^{[2
]}

Jiang, Tao

Levi, Moshe ^{[2
]}

Pruzanski, Mark ^{[3
]}

Adorini, Luciano ^{[1
]}

机构：

[1] Intercept Pharmaceut, I-06073 Perugia, Italy

[2] Univ Colorado, Dept Med, Denver, CO USA

[3] Intercept Pharmaceut, New York, NY USA

来源：

MOLECULAR PHARMACOLOGY | 2010年 / 78卷 / 04期

基金：

美国国家卫生研究院;

关键词：

NUCLEAR RECEPTOR; FXR; IDENTIFICATION; ACTIVATION; ADIPOCYTE; PROMOTER; LIGANDS; SHP;

D O I：

10.1124/mol.110.064501

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 6 alpha-ethyl-3 alpha, 7 alpha-dihydroxy-5 beta-cholan-24-oic acid (INT-747), a potent and selective FXR agonist, as well as 6 alpha-ethyl-23(S)-methyl-3 alpha, 7 alpha, 12 alpha-trihydroxy-5 beta-cholan-24-oic acid (INT-777), a potent and selective TGR5 agonist. Here we characterize 6 alpha-ethyl-3 alpha, 7 alpha, 23-trihydroxy-24-nor-5 beta-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 EC50, 30 nM by PerkinElmer AlphaScreen assay) and TGR5 (mean EC50, 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.

引用

页码：617 / 630

页数：14

共 43 条

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