INT-767是一种强效的法尼醇X受体（FXR）和Takeda G蛋白偶联受体5（TGR5）双重激动剂，EC50值分别为30nM和630nM。
Cas No.:1000403-03-1
Sample solution is provided at 25 µL, 10mM.
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INT-767 is a potent dual agonist of the farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5), with EC50 values of 30nM and 630nM, respectively[1,2]. INT-767 reduces hepatic lipids, improves insulin resistance, and alleviates inflammation, and is commonly used in the treatment and research of non-alcoholic steatohepatitis (NASH) and other metabolic diseases[3,4].
In vitro, treatment of rabbit visceral fat preadipocytes (rPADs) with INT-767 (1μM) for 10 days significantly increased oxygen consumption (from 30.83 ± 3.15 to 69.44 ± 14.74 nmol O2/mL) while decreasing ATP production (from 13.89 ± 0.92 to 9.34 ± 0.59 relative light units (RLU)/cell number)[5].
In vivo, oral administration of INT-767 (10mg/kg; once daily) for 8 weeks in ob/ob mice with NASH reduced hepatic collagen content and lipid area[6]. Treatment of NASH rats with INT-767 (20mg/kg; once daily) by gavage for 4 weeks significantly improved insulin resistance, as indicated by a reduced homeostatic model assessment of insulin resistance index (HOMA-IR) and increased serum glucagon-like peptide-1 (GLP-1) levels [7].
References:
[1] BAGHDASARYAN A, CLAUDEL T, GUMHOLD J, et al. Dual farnesoid X receptor/TGR5 agonist INT-767 reduces liver injury in the Mdr2-/-(Abcb4-/-) mouse cholangiopathy model by promoting biliary HCO output[J]. Hepatology, 2011, 54(4): 1303-1312.
[2] RIZZO G, PASSERI D, DE FRANCO F, et al. Functional characterization of the semisynthetic bile acid derivative INT-767, a dual farnesoid X receptor and TGR5 agonist[J]. Molecular Pharmacology, 2010, 78(4): 617-630.
[3] VIGNOZZI L, CELLAI I, FILIPPI S, et al. HP-01-006 The dual FXR/TGR5 agonist INT-767 counteracts nonalcoholic steatohepatitis and erectile dysfunction in a rabbit model of high fat diet-induced metabolic syndrome[J]. The Journal of Sexual Medicine, 2017, 14(Supplement 4a): e143-e144.
[4] WANG X X, LUO Y, WANG D, et al. A dual agonist of farnesoid X receptor (FXR) and the G protein–coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice[J]. Journal of Biological Chemistry, 2017, 292(29): 12018-12024.
[5] COMEGLIO P, CELLAI I, MELLO T, et al. INT-767 prevents NASH and promotes visceral fat brown adipogenesis and mitochondrial function[J]. Journal of Endocrinology, 2018, 238(2): 107-127.
[6] ROTH J D, FEIGH M, VEIDAL S S, et al. INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy-confirmed non-alcoholic steatohepatitis[J]. World Journal of Gastroenterology, 2018, 24(2): 195.
[7] HU Y B, LIU X Y, ZHAN W. Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis[EB/OL]. Drug Des Dev Ther, 2018, 12: 2213-2221.
INT-767是一种强效的法尼醇X受体（FXR）和Takeda G蛋白偶联受体5（TGR5）双重激动剂，EC50值分别为30nM和630nM[1,2]。INT-767可减少肝脂、改善胰岛素抵抗和缓解炎症，通常用于非酒精性脂肪性肝炎（NASH）和其它代谢疾病的治疗和研究[3,4]。
在体外，INT-767（1μM）处理兔内脏脂肪前体细胞rPADs 10天，显著提高了氧消耗量（从30.83 ± 3.15增加至69.44 ± 14.74 nmol O2/mL），同时降低了ATP生成（从13.89 ± 0.92降至9.34 ± 0.59 相对光单位（RLU）/细胞数）[5]。
在体内，INT-767（10mg/kg; once daily）通过口服治疗NASH的ob/ob小鼠8周，降低了肝脏胶原蛋白含量和脂质面积[6]。INT-767（20mg/kg; once daily）通过灌胃治疗NASH大鼠4周，可显著改善胰岛素抵抗，胰岛素抵抗指数（HOMA-IR）降低，血清胰高血糖素样肽-1（GLP-1）水平升高[7]。
| Cell experiment [1]: | |
Cell lines | rPADs |
Preparation Method | rPADs isolated from high-fat diet (HFD) rabbits were treated with 1μM INT-767 for 10 days, then oxygen consumption was measured using the Oxygraph system, and intracellular ATP levels were quantified using the CellTiter-Glo luminescent cell viability assay. |
Reaction Conditions | 1μM; 10 days |
Applications | INT-767 treatment (1µM) determined a significant increase, when compared to untreated HFD rPADs of oxygen consumption (HFD: 30.83 ± 3.15 nmol O2/mL; HFD + INT-767 1µM: 69.44 ± 14.74 nmol O2/mL), as well as a reduction of ATP formation (HFD: 13.89 ± 0.92 RLU/cell number; HFD + INT-767 1µM: 9.34 ± 0.59 RLU/cell number). |
| Animal experiment [2]: | |
Animal models | NASH male Sprague-Dawley rats |
Preparation Method | Male SD rats were fed a high-fat diet for 16 weeks to establish a NASH model. From week 13 to week 16, INT-767 (20mg/kg) was administered once daily by gavage. At the end of treatment, serum samples were collected. Fasting insulin levels were measured using a rat insulin ELISA kit, and fasting blood glucose levels were measured using a glucose meter. Insulin resistance was assessed by the homeostasis model assessment of HOMA-IR. GLP-1 levels were measured using a GLP-1 total ELISA kit. |
Dosage form | 20mg/kg; once daily; 4 weeks; i.g. |
Applications | Treatment of INT-767 can significantly improve insulin resistance, reduce HOMA-IR, and increase GLP-1 levels. |
References: | |
| Cas No. | 1000403-03-1 | SDF | |
| Canonical SMILES | C[C@H](CCOS(=O)([O-])=O)[C@@]1([H])CC[C@@]2([H])[C@]3([H])[C@H](O)[C@H](CC)[C@]4([H])C[C@H](O)CC[C@]4(C)[C@@]3([H])CC[C@@]21C.[Na+] | ||
| 分子式 | C25H43NaO6S | 分子量 | 494.66 |
| 溶解度 | DMSO : ≥ 205.5 mg/mL (415.44 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.0216 mL | 10.108 mL | 20.2159 mL |
| 5 mM | 404.3 μL | 2.0216 mL | 4.0432 mL |
| 10 mM | 202.2 μL | 1.0108 mL | 2.0216 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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