BVT 2733
目录号 : GC15738
An 11β-HSD1 inhibitor
Cas No.:376640-41-4
Sample solution is provided at 25 µL, 10mM.
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| Cell experiment [1]: | |
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Cell lines |
Mouse reticulum cell sarcoma-derived cell, J774.1 |
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Preparation Method |
J774.1 macrophages were activated by PA or LPS and co-treated with 11β-HSD1 inhibitor BVT 2733 (25-100 µmol/L) for 24 h. |
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Reaction Conditions |
25-100 µM BVT 2733 for 24h |
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Applications |
BVT 2733 attenuated the mRNA levels of MCP-1 and IL-6 in PA or LPS treated J774A.1 macrophages. The protein levels of MCP-1 and IL-6 in the medium were also attenuated. |
| Animal experiment [2]: | |
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Animal models |
Male C57BL/6J mice at age of 18 days |
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Preparation Method |
From 3 weeks of age, all mice were fed with a normal chow diet containing 10% calory from fat (NC mice), or a high fat diet (HFD) containing 50% calorie from fat for 24 weeks. During the last four weeks the HFD-fed mice were dosed with BVT 2733 (100 mg/kg, orally) (HFD+BVT mice) or vehicle (HFD mice). |
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Dosage form |
BVT 2733 (100 mg/kg, orally) for 4 weeks |
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Applications |
BVT 2733 administration normalized the expression profile of adiponkines by up-regulating the mRNA levels of adiponectin and vaspin and down-regulating the expression of resistin in adipose tissue. In line with these changes in adipose tissue serum levels of adiponectin and leptin were also improved by BVT 2733 treatment. |
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References: [1]. Wang L, Liu J, et,al. BVT.2733, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice. PLoS One. 2012;7(7):e40056. doi: 10.1371/journal.pone.0040056. Epub 2012 Jul 2. PMID: 22768329; PMCID: PMC3388048. | |
BVT 2733 is a novel, small-molecule, nonsteroidal, isoform-selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) with IC50 of 96 nM (mice)[1].
BVT 2733 attenuated the mRNA levels of MCP-1 and IL-6 in PA or LPS treated J774A.1 macrophages. The protein levels of MCP-1 and IL-6 in the medium were also attenuated[2]. After constructing the mouse 11β-HSD1 overexpression lentiviral vector, MC3T3-E1 preosteoblasts were infected with negative control lentivirus and overexpressing 11β-HSD1 lentivirus, respectively, and then added with the selective inhibitor of 11β-HSD1 BVT 2733 to reverse the inhibitory effect of 11β-HSD1 expression on osteogenesis[6]. A significant increase in the expression of BAT-specific genes, including UCP1, Cidea, Cox7a1 and Cox8b, was observed in BVT 2733 treated and 11β-HSD1-deficient mouse native brown adipocytes[7].
BVT 2733 administration normalized the expression profile of adiponkines by up-regulating the mRNA levels of adiponectin and vaspin and down-regulating the expression of resistin in adipose tissue. In line with these changes in adipose tissue serum levels of adiponectin and leptin were also improved by BVT 2733 treatment[2]. BVT 2733 treatment attenuated the arthritis severity and anti-CII level in CIA mice. BVT-2733 also decreased the levels of serum TNF-α, IL-1β, IL-6 and IL-17. BVT 2733 treatment also significantly reduced synovial inflammation and joint destruction[3]. In hyperglycemic, but not in normal mice, BVT 2733 lowered circulating glucose and insulin levels. In oral glucose tolerance tests in ob/ob and KKAy mice, glucose concentrations were 65-75% of vehicle values after BVT 2733 treatment, and in KKAy mice insulin concentrations were decreased[4]. BVT 2733 reduced food intake but prevented a concomitant reduction in lean body mass and energy expenditure. The latter effects may have contributed to improved glucose tolerance[5].
References:
[1]: Alberts P, Engblom L, et,al. Selective inhibition of 11beta-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia. 2002 Nov;45(11):1528-32. doi: 10.1007/s00125-002-0959-6. Epub 2002 Sep 18. PMID: 12436336.
[2]: Wang L, Liu J, et,al. BVT.2733, a selective 11β-hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice. PLoS One. 2012;7(7):e40056. doi: 10.1371/journal.pone.0040056. Epub 2012 Jul 2. PMID: 22768329; PMCID: PMC3388048.
[3]: Zhang L, Dong Y, et,al. 11β-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis. Int Immunopharmacol. 2013 Nov;17(3):489-94. doi: 10.1016/j.intimp.2013.07.015. Epub 2013 Aug 11. PMID: 23938253.
[4]: Alberts P, Nilsson C, et,al. Selective inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology. 2003 Nov;144(11):4755-62. doi: 10.1210/en.2003-0344. Epub 2003 Jul 31. PMID: 12960099.
[5]: Wang SJ, Birtles S, et,al. Inhibition of 11beta-hydroxysteroid dehydrogenase type 1 reduces food intake and weight gain but maintains energy expenditure in diet-induced obese mice. Diabetologia. 2006 Jun;49(6):1333-7. doi: 10.1007/s00125-006-0239-y. Epub 2006 Apr 13. PMID: 16612591.
[6]: Wu L, Qi H, et,al. 11β-Hydroxysteroid dehydrogenase type 1 selective inhibitor BVT.2733 protects osteoblasts against endogenous glucocorticoid induced dysfunction. Endocr J. 2013;60(9):1047-58. doi: 10.1507/endocrj.ej12-0376. Epub 2013 Jun 12. PMID: 23759754.
[7]: Liu J, Kong X, et,al. Essential roles of 11β-HSD1 in regulating brown adipocyte function. J Mol Endocrinol. 2013 Jan 11;50(1):103-13. doi: 10.1530/JME-12-0099. PMID: 23197361.
BVT 2733 是一种新型、小分子、非甾体、异构体选择性 11β-羟基类固醇脱氢酶 1 型 (11β-HSD1) 抑制剂，IC50 为 96 nM（小鼠）[1]。
BVT 2733 减弱了 PA 或 LPS 处理的 J774A.1 巨噬细胞中 MCP-1 和 IL-6 的 mRNA 水平。培养基中 MCP-1 和 IL-6 的蛋白水平也降低了[2]。构建小鼠11β-HSD1过表达慢病毒载体后，MC3T3-E1前成骨细胞分别感染阴性对照慢病毒和过表达11β-HSD1慢病毒，然后加入11β-HSD1选择性抑制剂BVT 2733逆转11β的抑制作用-HSD1 在成骨过程中的表达[6]。在 BVT 2733 处理和 11β-HSD1 缺陷的小鼠天然棕色脂肪细胞中观察到 BAT 特异性基因（包括 UCP1、Cidea、Cox7a1 和 Cox8b）的表达显着增加[7]。\n
BVT 2733 给药通过上调脂联素和 vaspin 的 mRNA 水平以及下调脂肪组织中抵抗素的表达来使脂联素的表达谱正常化。与脂肪组织的这些变化一致，BVT 2733 治疗也改善了脂联素和瘦素的血清水平[2]。 BVT 2733 治疗减轻了 CIA 小鼠的关节炎严重程度和抗 CII 水平。 BVT-2733 还降低了血清 TNF-α、IL-1β、IL-6 和 IL-17 的水平。 BVT 2733 治疗还显着减少了滑膜炎症和关节破坏[3]。在高血糖症小鼠中，但在正常小鼠中，BVT 2733 降低了循环葡萄糖和胰岛素水平。在 ob/ob 和 KKAy 小鼠的口服葡萄糖耐量试验中，BVT 2733 处理后葡萄糖浓度为载体值的 65-75%，并且在 KKAy 小鼠中胰岛素浓度降低[4]。 BVT 2733 减少了食物摄入量，但阻止了随之而来的瘦体重和能量消耗的减少。后一种作用可能有助于改善葡萄糖耐量[5]。
| Cas No. | 376640-41-4 | SDF | |
| 化学名 | 3-chloro-2-methyl-N-(4-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)thiazol-2-yl)benzenesulfonamide | ||
| Canonical SMILES | CC1=C(Cl)C=CC=C1S(NC2=NC(CC(N3CCN(CC3)C)=O)=CS2)(=O)=O | ||
| 分子式 | C17H21ClN4O3S2 | 分子量 | 428.96 |
| 溶解度 | ≥ 42.9mg/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 | 2.3312 mL | 11.6561 mL | 23.3122 mL |
| 5 mM | 0.4662 mL | 2.3312 mL | 4.6624 mL |
| 10 mM | 0.2331 mL | 1.1656 mL | 2.3312 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 | ||||||||||
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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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BVT.2733, a selective 11 hydroxysteroid dehydrogenase type 1 inhibitor, attenuates obesity and inflammation in diet-induced obese mice
PLoS One2012;7(7):e40056.PMID: 22768329DOI: 10.1371/journal.pone.0040056
Background: Inhibition of 11 hydroxysteroid dehydrogenase type 1 (11 HSD1) is being pursued as a new therapeutic approach for the treatment of obesity and metabolic syndrome. Therefore, there is an urgent need to determine the effect of 11 HSD1 inhibitor, which suppresses glucocorticoid action, on adipose tissue inflammation. The purpose of the present study was to examine the effect of BVT.2733, a selective 11 HSD1 inhibitor, on expression of pro-inflammatory mediators and macrophage infiltration in adipose tissue in C57BL/6J mice. Methodology/principal findings: C57BL/6J mice were fed with a normal chow diet (NC) or high fat diet (HFD). HFD treated mice were then administrated with BVT.2733 (HFD+BVT) or vehicle (HFD) for four weeks. Mice receiving BVT.2733 treatment exhibited decreased body weight and enhanced glucose tolerance and insulin sensitivity compared to control mice. BVT.2733 also down-regulated the expression of inflammation-related genes including monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor alpha (TNF- Á) and the number of infiltrated macrophages within the adipose tissue in vivo. Pharmacological inhibition of 11 HSD1 and RNA interference against 11 HSD1 reduced the mRNA levels of MCP-1 and interleukin-6 (IL-6) in cultured J774A.1 macrophages and 3T3-L1 preadipocyte in vitro. Conclusions/significance: These results suggest that BVT.2733 treatment could not only decrease body weight and improve metabolic homeostasis, but also suppress the inflammation of adipose tissue in diet-induced obese mice. 11 HSD1 may be a very promising therapeutic target for obesity and associated disease.
[Mechanism of BVT.2733 and pioglitazone in the improvement of insulin resistance]
Zhonghua Nei Ke Za Zhi2008 Nov;47(11):938-41.PMID: 19080239DOI: 10.2147/DDDT.S285828
Objective: To investigate the mechanism of BVT.2733 on insulin resistance, by using diet-induced obese (DIO) mice model.
Methods: After having been balanced for 3 days, the C57BL/6J mice were randomly divided into a normal diet group and a high-fat diet (HFD) group. After 20 weeks, the obese mice were further randomly divided into an obese control group, a BVT.2733 group and a pioglitazone (PGZ) group and they were orally administered with placebo, BVT.2733 and PGZ separately for two weeks. Adiponectin and leptin mRNA expression levels from adipose tissue were analyzed with real-time quantitative PCR. The levels of plasma glucose, serum insulin and adiponectin were measured with biochemical technology, radioimmunoassay and ELISA. Adipocyte sizes were observed with immunohistochemistry.
Results: The body weight, plasma glucose and serum insulin levels raised (P < 0.05) in the HFD group and the adipocyte sizes were bigger. Serum insulin levels significantly reduced (P < 0.05) and adipocyte sizes reduced, while plasma adiponectin level raised (P < 0.01) in the two treatment groups as compared with those in obese controls. Both the mRNA expressions of adiponectin and leptin upregulated (P < 0.05) in the PGZ group, but their expressions in the BVT.2733 group did not alter significantly. The body weight of the mice reduced significantly in the BVT.2733 group.
Conclusion: BVT.2733 can reduce body weight significantly and improve insulin resistance, but cannot influence the expression of adipocytokines.
Selective Inhibition of 11 Hydroxysteroid Dehydrogenase Type 1 Attenuates High-Fat Diet-Induced Hepatic Steatosis in Mice
Drug Des Devel Ther2021 May 31;15:2309-2324.PMID: 34103895DOI: 10.2147/DDDT.S285828
Introduction: The effect of 11 hydroxysteroid dehydrogenase type1 (11 HSD1) inhibition on hepatic steatosis is incompletely understood. Here, we aimed to determine the therapeutic effect of BVT.2733, a selective 11 HSD1 inhibitor, on hepatic steatosis.
Materials and methods: C57B/6J mice were randomly divided into a low-fat diet (LFD) fed group and a high-fat diet (HFD) fed group. Mice were fed with HFD for 28 weeks which induced obesity and severe hepatic steatosis. The two groups were further divided into four groups as follows: LFD, LFD with BVT.2733, HFD, and HFD with BVT.2733. Mice in LFD+BVT and HFD+BVT groups were intraperitoneally injected with BVT.2733 daily for 30 days. Effects of BVT.2733 on mice body weight, serum lipid profile, serum free fatty acids (FFAs), glucocorticoid levels, gene expression in adipose and liver tissues were assessed.
Results: Injection of a low dose of BVT.2733 (50 mg/kg/day) reduced body weight and hyperlipidemia, but did not improve glucose tolerance and insulin resistance in diet-induced obese mice. The low dose of BVT.2733 attenuated hepatic steatosis, liver injury, and liver lipolytic gene expression in diet-induced obese mice. Besides, the low dose of BVT.2733 reduced fat mass and lipolysis in visceral adipose tissues, hepatic FFAs, and serum corticosterone levels in diet-induced obese mice.
Conclusion: Our study shows that moderate inhibition of 11 HSD1 by BVT.2733 reduces FFAs and corticosterone synthesis in fatty tissues, thereby attenuates the delivery of corticosterone and FFAs to the liver. Collectively, this prevents high-fat diet-induced hepatic steatosis.
11 Hydroxysteroid dehydrogenase type 1 selective inhibitor BVT.2733 protects osteoblasts against endogenous glucocorticoid induced dysfunction
Endocr J2013;60(9):1047-58.PMID: 23759754DOI: 10.1507/endocrj.ej12-0376
Pharmacologic glucocorticoids (GCs) inhibit osteoblast function and induce osteoporosis. 11 hydroxysteroid dehydrogenase type 1 (11 HSD1) may play a role in osteoporosis as it regulates GC action at a pre-receptor level by converting inactive GC to its active form. Further, 11 HSD1 was found increasingly expressed in bone with age. In spite of these observations, its function in senile osteoporosis remains uncertain. In this study we constructed a lentiviral vector overexpressing mouse 11 HSD1 and then MC3T3-E1 preosteoblast cells were infected by the negative control lentivirus and 11 HSD1-overexpressing lentivirus, respectively. The mRNA and protein levels of 11 HSD1 were significantly increased in MC3T3-E1 cells that were infected by 11 HSD1-overexpressing lentivirus compared to the cells infected by the negative control lentivirus. The osteogenic differentiation of MC3T3-E1 preosteoblast cells was dramatically suppressed by 11 HSD1 overexpression under the reductase substrate dehydrocorticosterone (DHC). The inhibition effect was similar to the inhibition of osteogenesis by over-dose GCs, including ALP activity, the ultimate calcium nodus formation as well as the expression of the osteogenic genes such as ALP, BSP, OPN and OCN. However, with addition of BVT.2733, a selective inhibitor of 11 HSD1, all of the above osteogenic repression effects by 11 HSD1 overexpression were reversed. Furthermore, a GC receptor antagonist RU486 also showed the similar effect, preventing inhibition of osteogenesis by 11 HSD1 overexpression. These results demonstrated that the specific 11 HSD1 inhibitor BVT.2733 can reverse the suppression effect towards osteogenic differentiation in 11 HSD1 overexpressed MC3T3-E1 cells. Inhibition of 11 HSD1 can be a new therapeutic strategy for senile osteoporosis.