title: 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.affiliation: Intercept Pharmaceuticals Italia Srl, Via Togliatti, 06073, Corciano, Perugia, Italia. grizzo@interceptpharma.com
authors.forename: Giovanni
authors.initials: G
authors.lastname: Rizzo
authors.forename: Daniela
authors.initials: D
authors.lastname: Passeri
authors.forename: Francesca
authors.initials: F
authors.lastname: De Franco
authors.forename: Gianmario
authors.initials: G
authors.lastname: Ciaccioli
authors.forename: Loredana
authors.initials: L
authors.lastname: Donadio
authors.forename: Giorgia
authors.initials: G
authors.lastname: Rizzo
authors.forename: Stefano
authors.initials: S
authors.lastname: Orlandi
authors.forename: Bahman
authors.initials: B
authors.lastname: Sadeghpour
authors.forename: Xiaoxin X
authors.initials: XX
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
authors.forename: Mark
authors.initials: M
authors.lastname: Pruzanski
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008820:Mice, Obese; D041681:NIH 3T3 Cells; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D000099150:Receptor, Farnesoid X-Activated; C000602622:6-ethyl-24-norcholane-3,7,23-triol-23 sulfate; C473772:GPBAR1 protein, human