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| Targets |
INT-767 sodium targets the farnesoid X receptor (FXR) and the TGR5 receptor (also known as GPBAR1). FXR is a nuclear receptor that regulates the expression of genes involved in bile acid synthesis, lipid metabolism, and glucose homeostasis. TGR5 is a G protein-coupled receptor that is activated by bile acids and plays a role in energy metabolism, inflammation, and insulin secretion. INT-767 acts as an agonist at both receptors, with higher potency at FXR (EC50 = 30 nM) compared to TGR5 (EC50 = 630 nM).
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| ln Vitro |
INT-767 is very stable to phase I and phase II enzymatic changes, does not inhibit cytochrome P450 enzymes, does not show cytotoxic effects in HepG2 cells, and does not block potassium channels associated to the human ether-a-go-go gene [2].
In vitro, INT-767 is a dual FXR/TGR5 agonist with mean EC50s of 30 and 630 nM, respectively. It 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. These properties suggest a favorable safety profile for in vitro studies. The compound's activity at FXR and TGR5 makes it a valuable tool for studying bile acid signaling and metabolic regulation. |
| ln Vivo |
In db/m and db/db mice, INT-767 (10–20 mg/kg; i.p.; once daily for two weeks) lowers plasma total cholesterol and triglyceride levels [2].
In vivo, INT-767 (10-20 mg/kg; intraperitoneal; daily for 2 weeks) decreases plasma total cholesterol and triglyceride levels in db/m and db/db mice. It has been planned for a Phase II trial for hepatic fibrosis. The compound's dual FXR/TGR5 agonism may offer therapeutic benefits for non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and other metabolic disorders by improving lipid profiles, reducing inflammation, and enhancing insulin sensitivity. |
| Enzyme Assay |
Non-cellular in vitro assays for INT-767 involve measuring its agonist activity at FXR and TGR5. For FXR, a typical protocol uses a cell-free transcription assay where the FXR ligand-binding domain is incubated with a biotinylated coactivator peptide and varying concentrations of INT-767. The interaction is detected using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. For TGR5, a membrane-based GTPγS binding assay is used. Membranes from cells expressing TGR5 are incubated with [³⁵S]GTPγS and varying concentrations of INT-767. The amount of bound radioactivity is measured, and the EC50 is determined.
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| Cell Assay |
Cellular assays for INT-767 are performed using cell lines expressing FXR or TGR5, such as HepG2 hepatocytes (for FXR) or CHO cells stably transfected with TGR5. Cells are treated with INT-767 at various concentrations for 6-24 hours. FXR activation is assessed by measuring the expression of FXR target genes (e.g., SHP, BSEP) by RT-PCR. TGR5 activation is assessed by measuring intracellular cAMP accumulation using an ELISA or HTRF assay. The EC50 for receptor activation is determined from the concentration-response curve.
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| Animal Protocol |
Animal/Disease Models: Male 8weeks old C57BKS/J db/db mice, control non-diabetic db/m mice [2]
Doses: 10, 20 mg/kg Route of Administration: intraperitoneal (ip) injection; one time/day for 2 weeks Experimental Results: Plasma total cholesterol and triglyceride levels were diminished. In vivo animal studies for INT-767 are conducted in mouse models of metabolic disease, such as db/db mice (a model of type 2 diabetes and obesity) or diet-induced obese (DIO) mice. INT-767 is administered intraperitoneally at doses of 10-20 mg/kg daily for 2 weeks. Blood samples are collected for analysis of plasma total cholesterol and triglyceride levels. Liver tissues are harvested for histological examination and analysis of gene expression. The compound's effects on glucose tolerance and insulin sensitivity may also be assessed. |
| ADME/Pharmacokinetics |
INT-767 sodium has a molecular weight of 494.66 and a molecular formula of C25H43NaO6S. It is a solid powder with a purity of ≥98%. It is soluble in DMSO at ≥100 mg/mL (202.16 mM). For storage, it should be kept dry, dark, and at -20°C for up to 1 year. It can be stored in solution at 0-4°C for up to 1 month. Detailed pharmacokinetic parameters have not been fully reported, but its efficacy in animal models suggests it has sufficient bioavailability.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for INT-767 have not been extensively reported. In vitro studies indicate that it does not show cytotoxic effects in HepG2 cells, does not inhibit cytochrome P450 enzymes, and does not inhibit the hERG potassium channel. As a research chemical, it is not intended for human use and is strictly for preclinical research purposes. Standard safety precautions should be followed when handling INT-767. No specific toxicity data, such as LD50 values, are available in the provided literature.
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| References |
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| Additional Infomation |
See also: Int-767 (comment moved to).
INT-767 is a dual FXR/TGR5 agonist with mean EC50s of 30 and 630 nM, respectively. It has been investigated for its potential in treating liver and metabolic diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The compound was planned for a Phase II trial for hepatic fibrosis. INT-767 is not a clinically approved drug. Its primary application is in academic and pharmaceutical research to study FXR and TGR5 signaling and to validate these receptors as therapeutic targets for metabolic and liver diseases. |
| Molecular Formula |
C25H43NAO6S
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| Molecular Weight |
494.660098314285
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| Exact Mass |
494.267
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| CAS # |
1000403-03-1
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| Related CAS # |
1000403-03-1 (sodium);1000403-00-8 (free);
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| PubChem CID |
23712772
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
786
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| Defined Atom Stereocenter Count |
11
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| SMILES |
CC[C@@H]1[C@@H]2C[C@@H](CC[C@@]2([C@H]3CC[C@]4([C@H]([C@@H]3[C@@H]1O)CC[C@@H]4[C@H](C)CCOS(=O)(=O)[O-])C)C)O.[Na+]
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| InChi Key |
TXIWHUPIUUZFFK-PMWRKVJASA-M
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| InChi Code |
InChI=1S/C25H44O6S.Na/c1-5-17-21-14-16(26)8-11-25(21,4)20-9-12-24(3)18(6-7-19(24)22(20)23(17)27)15(2)10-13-31-32(28,29)30;/h15-23,26-27H,5-14H2,1-4H3,(H,28,29,30);/q;+1/p-1/t15-,16-,17-,18-,19+,20+,21+,22+,23-,24-,25-;/m1./s1
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| Chemical Name |
sodium;[(3R)-3-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]butyl] sulfate
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| Synonyms |
INT 767 INT767INT-767 INT-767 Free
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ≥ 100 mg/mL (~202.16 mM)
H2O : ~100 mg/mL (~202.16 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.05 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.05 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.05 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 50 mg/mL (101.08 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0216 mL | 10.1080 mL | 20.2159 mL | |
| 5 mM | 0.4043 mL | 2.0216 mL | 4.0432 mL | |
| 10 mM | 0.2022 mL | 1.0108 mL | 2.0216 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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