GW4064
(Synonyms: 3-(2,6-二氯苯基)-4-(3'-羧基-2-氯二苯乙烯-4-基)氧甲基-5-异丙基异恶唑) 目录号 : GC10975
GW4064作为合成的FXR激动剂，用于治疗胆汁淤积性肝病、代谢综合征和酒精性肝病。
Cas No.:278779-30-9
Sample solution is provided at 25 µL, 10mM.
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GW4064, as a synthetic FXR agonist, was used for treatment of cholestatic liver diseases, metabolic syndrome and alcoholic liver disease.[1]
In vitro experiment it shown that the IC50 values of GW4064 in SW620 and HT-29 cells were 7.6 μM and 13.8 μM, respectively.[2] In vitro efficacy test it indicated that the GW4064 response was concentration dependent (EC50 values after 24 hours of treatment were 0.012 μM and 0.015 μM, respectively) on CRE and NFAT-RE luciferases.[3] GW4064 dose dependently enhanced the basal cAMP level with EC50 of 0.241 μM, and suppressed forskolin-induced cAMP accumulation with IC50 of 0.07 μM.[3]
In vivo study it demonstrated that Rats in the treatment group received an interperitoneal GW4064 injection of 30 mg/kg every other day for 2 wk, GW4064 could correct BA dysmetabolism to alleviate hepatotoxicity in SBR animals. In the meanwhile, GW4064 intervention decreased the fecal bile excretion and elevated plasma/hepatic conjugated BA levels. It also increased the reabsorption of conjugated BAs by inducing apical sodium-dependent bile salt transporter expression in the ileum.[4] In vivo, treatment with 30 mg/kg for 7 consecutive days intraperitoneally, GW4064 alleviated social deficits in BTBR mice and modulated selective aspects of the composition of the gut microbiota.[5] Mice were injected 20 mg/kg GW4064 intraperitoneally result in that decreased hepatic inflammation in the LPS-induced murine liver injury model.[6].
References:
[1]. A.S. Alawad, C. Levy. FXR agonists: from bench to bedside, a guide for clinicians Dig. Dis. Sci., 61 (12) (2016), pp. 3395-3404.
[2]. Guo J, et al. GW4064 enhances the chemosensitivity of colorectal cancer to oxaliplatin by inducing pyroptosis. Biochem Biophys Res Commun. 2021 Apr 9;548:60-66.
[3]. Singh N, et al. Synthetic FXR agonist GW4064 is a modulator of multiple G protein-coupled receptors. Mol Endocrinol. 2014 May;28(5):659-73.
[4]. Cao Y, et al. FXR agonist GW4064 improves liver and intestinal pathology and alters bile acid metabolism in rats undergoing small intestinal resection. Am J Physiol Gastrointest Liver Physiol. 2019 Aug 1;317(2):G108-G115.
[5]. Liu J, et al. GW4064 Alters Gut Microbiota Composition and Counteracts Autism-Associated Behaviors in BTBR T+tf/J Mice. Front Cell Infect Microbiol. 2022 Jun 22;12:911259.
[6]. Liu HM, et al. GW4064 attenuates lipopolysaccharide induced hepatic inflammation and apoptosis through inhibition of the Toll like receptor 4 mediated p38 mitogen activated protein kinase signaling pathway in mice. Int J Mol Med. 2018 Mar;41(3):1455-1462.
GW4064作为合成的FXR激动剂，用于治疗胆汁淤积性肝病、代谢综合征和酒精性肝病。[1]
体外实验表明GW4064在SW620和HT-29细胞中的IC50值分别为7.6 μM和13.8 μM。[2] 体外药效试验表明GW4064反应对 CRE 和 NFAT-RE 荧光素酶具有浓度依赖性（处理 24 小时后 EC50 值分别为 0.012 μM 和 0.015 μM）。[3] GW4064 剂量依赖性地增强基础 cAMP 水平，EC50 为 0.241 μM，并抑制毛喉素诱导的 cAMP 积累，IC50 为 0.07 μM。[3]
体内研究表明，治疗组的大鼠每隔一天接受 30 mg/kg 的 GW4064 腹腔注射，持续 2 周，GW4064 可以纠正 BA 代谢障碍，减轻 SBR 动物的肝毒性。同时，GW4064 干预减少了粪便胆汁排泄并升高了血浆/肝脏结合 BA 水平。它还通过在回肠中诱导顶端钠依赖性胆盐转运蛋白表达来增加结合 BA 的重吸收。[4] 在体内，连续 7 天腹膜内注射 30 mg/kg，GW4064 减轻了社会BTBR 小鼠的缺陷和调节肠道微生物群组成的选择性方面。[5] 小鼠腹膜内注射 20 mg/kg GW4064 导致 LPS 诱导的小鼠肝损伤模型中的肝脏炎症减少.[6].
| Cell experiment [1]: | |
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Cell lines |
HEK cells |
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Preparation Method |
HEK cells in chamber slides were treated with 1 μM GW4064 or ionomycin (I, 1 μM) for 30 minutes, and endogenous NFATc1 was detected by immunocytochemical analysis. The nuclei were stained with 4′,6-diamidino-2-phenylindole (DAPI). |
|
Reaction Conditions |
1 μM, 30 minutes |
|
Applications |
Consequent to calcineurin activation, nuclear translocation of endogenous NFATc1 was enhanced by GW4064 in a microscopy-based assay. |
| Animal experiment [2]: | |
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Animal models |
4-week-old female BALB/c-nude mice |
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Preparation Method |
HT-29 cells (5 × 106) in logarithmic growth phase were subcutaneously injected into the flanks of nude mice. When the palatable xenograft tumors were established, oxaliplatin (3 mg/kg) and GW4064 (15 mg/kg) as both single agents and in combination was injected intraperitoneally twice a week for 3 weeks. The tumor width (b) and length (a) were measured using the callipers every 3 days. |
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Dosage form |
15 mg/kg, i.p. |
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Applications |
Compared with using oxaliplatin or GW4064 only, combination of oxaliplatin and GW4064 in HT-29 cell line inhibited the tumor formation more significantly in vivo. |
|
References: [1]. Singh N, et al. Synthetic FXR agonist GW4064 is a modulator of multiple G protein-coupled receptors. Mol Endocrinol. 2014 May;28(5):659-73. [2]. Guo J, et al. GW4064 enhances the chemosensitivity of colorectal cancer to oxaliplatin by inducing pyroptosis. Biochem Biophys Res Commun. 2021 Apr 9;548:60-66. |
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| Cas No. | 278779-30-9 | SDF | |
| 别名 | 3-(2,6-二氯苯基)-4-(3'-羧基-2-氯二苯乙烯-4-基)氧甲基-5-异丙基异恶唑 | ||
| 化学名 | 3-[(E)-2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-propan-2-yl-1,2-oxazol-4-yl]methoxy]phenyl]ethenyl]benzoic acid | ||
| Canonical SMILES | CC(C)C1=C(C(=NO1)C2=C(C=CC=C2Cl)Cl)COC3=CC(=C(C=C3)C=CC4=CC(=CC=C4)C(=O)O)Cl | ||
| 分子式 | C28H22Cl3NO4 | 分子量 | 542.85 |
| 溶解度 | ≥ 24.7mg/mL in DMSO | 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.8421 mL | 9.2106 mL | 18.4213 mL |
| 5 mM | 0.3684 mL | 1.8421 mL | 3.6843 mL |
| 10 mM | 0.1842 mL | 0.9211 mL | 1.8421 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 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 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Quality Control & SDS
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- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
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