hPPARδ (EC50 = 20 μM); hPPARα (EC50 = 50 μM); hPPARγ (EC50 = 60 μM)

Bezafibrate 是一种 PPAR 激动剂。对于小鼠 PPARα、PPARγ 和 PPARδ，相应的 EC50 值为 90 μM、55 μM 和 110 μM。人 PPARα、PPARγ 和 PPARδ 的 EC50 值分别为 50 μM、60 μM 和 20 μM。是[1]。当应用于人视网膜色素上皮 ARPE-19 细胞和人视网膜微血管内皮细胞 (HRMEC) 时，苯扎贝特 (>200 μM) 表现出显着的细胞毒性。在 HRMEC 中，bezafibrate (30-100 μM) 可减少 TNFα 诱导的炎症因子并控制 TNFα 诱导的核因子 (NF)-κB 反式激活。 Bezafibrate 抑制 VEGF 引起的 HRMEC 迁移以及白细胞介素 (IL)-1β 刺激的 ARPE-19 细胞释放 VEGF [2]。

在 TallyHo 小鼠中，苯扎贝特 (0.5%) 显着降低血浆脂质和葡萄糖水平，并增加胰岛的大小。苯扎贝特还可以增强代谢灵活性和能量消耗。苯扎贝特还可以增强脂肪变性，改变脂质的组成，并增加肝脏中线粒体的质量[3]。

苯扎贝特是一种贝特类药物，通常用作治疗高脂血症的降脂剂，并作为所有PPAR亚型的泛激动剂。然而，苯扎贝特对糖尿病视网膜病变的影响尚不清楚。因此，本研究旨在探讨苯扎贝特对视网膜微血管炎症的影响。苯扎贝特对分别用<100和200μM苯扎贝特处理的人视网膜微血管内皮细胞（HRMECs）和人视网膜色素上皮细胞（ARPE-19细胞）没有细胞毒性。在HRMECs中，苯扎贝特以剂量依赖的方式显著抑制了肿瘤坏死因子（TNF）-α诱导的单核细胞趋化蛋白（MCP）-1、细胞间粘附分子（ICAM）-1和血管细胞粘附分子（VCAM）-1的表达水平。在苯扎贝特处理的HRMECs中，TNF-α诱导的核因子（NF）-κB p65的核转位和细胞迁移也受到显著抑制。此外，苯扎贝特治疗显著抑制了白细胞介素（IL）-1β诱导的ARPE-19细胞中血管内皮生长因子（VEGF）的产生。这些结果表明，苯扎贝特对视网膜微血管炎症具有有益作用。我们的研究证明了苯扎贝特在治疗糖尿病视网膜病变方面的治疗潜力[2]。

TallyHo mice were divided into an early (ED) and late (LD) diabetes progression group and both groups were treated with 0.5% Bezafibrate (BEZ) (BEZ group) or standard diet (SD group) for 8 weeks. We analyzed plasma parameters, pancreatic beta-cell morphology, and mass as well as glucose metabolism of the BEZ-treated and control mice. Furthermore, liver fat content and composition as well as hepatic gluconeogenesis and mitochondrial mass were determined.[3]

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TallyHo mice are bred in our animal facility. Only male mice are used in the study, and mice receive a standard diet (SD), which is supplemented with 0.5% (w/w) Bezafibrate for the Bezafibrate groups for 8 weeks. Animals are killed by isoflurane overdose, and dissected tissues are prepared as stated below. All data represent samples taken after 8 weeks of Bezafibrate (or SD) treatment unless otherwise stated

Rats and mice

Absorption, Distribution and Excretion
Bezafibrate is almost completely absorbed after oral administration. The relative bioavailability of bezafibrate retard compared to the standard form is about 70%.

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Metabolism / Metabolites
Hepatic.

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Biological Half-Life
1-2 hours

Protein Binding
94-96% of bezafibrate is bound to protein in human serum.

[1]. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000 Feb 24;43(4):527-50.

[2]. The peroxisome proliferator-activated receptor pan-agonist bezafibrate suppresses microvascular inflammatory responses of retinal endothelial cells and vascular endothelial growth factor production in retinal pigmented epithelial cells. Int Immunopharmacol. 2017 Nov;52:70-76.

[3]. Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice. Mol Metab. 2017 Jan 6;6(3):256-266.

Bezafibrate is a monocarboxylic acid amide obtained by the formal condensation of the carboxy group of 4-chlorobenzoic acid with the amino group of 2-[4-(2-aminoethyl)phenoxy]-2-methylpropanoic acid. Benafibrate is used for the treatment of hyperlipidaemia. It has a role as a xenobiotic, an environmental contaminant, a geroprotector and an antilipemic drug. It is a monocarboxylic acid, an aromatic ether, a member of monochlorobenzenes and a monocarboxylic acid amide. It is functionally related to a propionic acid.
Antilipemic agent that lowers cholesterol and triglycerides. It decreases low density lipoproteins and increases high density lipoproteins.
Bezafibrate is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha) with antilipidemic activity. Bezafibrate decreases triglyceride levels, increases high density lipoprotein (HDL) cholesterol levels, and decreases total and low density lipoprotein (LDL) cholesterol levels.
An antilipemic agent that lowers CHOLESTEROL and TRIGLYCERIDES. It decreases LOW DENSITY LIPOPROTEINS and increases HIGH DENSITY LIPOPROTEINS.

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Drug Indication
For the treatment of primary hyperlipidaemia types IIa, IIb, III, IV and V (Fredrickson classification) corresponding to groups I, II and III of the European Atherosclerosis Society guidelines - when diet alone or improvements in lifestyle such as increased exercise or weight reduction do not lead to an adequate response. Also for the treatment of secondary hyperlipidaemias, e.g. severe hypertriglyceridemias, when sufficient improvement does not occur after correction of the underlying disorder (e.g. diabetes mellitus).

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Mechanism of Action
It is generally accepted that bezafibrate is likely an agonist of PPAR-alpha. However, certain other investigations have also suggested that the substance might also elicit some effects on PPAR-gamma and PPAR-delta too.

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Pharmacodynamics
Bezafibrate is an antilipemic agent that lowers cholesterol and triglycerides. It decreases low density lipoproteins and increases high density lipoproteins. Bezafibrate lowers elevated blood lipids (triglycerides and cholesterol). Elevated VLDL and LDL are reduced by treatment with bezafibrate, whilst HDL-levels are increased. The activity of triglyceride lipases (lipoprotein lipase and hepatic lipoproteinlipase) involved in the catabolism of triglyceride-rich lipoproteins is increased by bezafibrate. In the course of the intensified degradation of triglyceride-rich lipoproteins (chylomicrons, VLDL) precursors for the formation of HDL are formed which explains an increase in HDL. Furthermore, cholesterol biosynthesis is reduced by bezafibrate, which is accompanied by a stimulation of the LDL-receptor-mediated lipoprotein catabolism. Elevated fibrinogen appears to be an important risk-factor, alongside the lipids, smoking and hypertension, in the development of atheroma. Fibrinogen plays an important role in viscosity, and therefore blood flow, and also appears to play an important role in thrombus development and lysability. Bezafibrate exerts an effect on thrombogenic factors. A significant decrease in elevated plasma fibrinogen levels can be achieved. This may lead, amongst other things, to a reduction in both blood and plasma viscosity. Inhibition of platelet aggregation has also been observed. A reduction in blood glucose concentration due to an increase in glucose tolerance has been reported in diabetic patients. In the same patients, the concentration of fasting and postprandial free fatty acids was reduced by bezafibrate.

C19H20CLNO4

361.82

361.108

C, 63.07; H, 5.57; Cl, 9.80; N, 3.87; O, 17.69

41859-67-0

Bezafibrate-d6;1219802-74-0;Bezafibrate-d4;1189452-53-6

39042

White to off-white solid powder

1.3±0.1 g/cm3

572.1±45.0 °C at 760 mmHg

184 °C

299.8±28.7 °C

0.0±1.7 mmHg at 25°C

1.583

3.46

75.63

2

4

7

25

452

0

ClC1C([H])=C([H])C(=C([H])C=1[H])C(N([H])C([H])([H])C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])OC(C(=O)O[H])(C([H])([H])[H])C([H])([H])[H])=O

IIBYAHWJQTYFKB-UHFFFAOYSA-N

InChI=1S/C19H20ClNO4/c1-19(2,18(23)24)25-16-9-3-13(4-10-16)11-12-21-17(22)14-5-7-15(20)8-6-14/h3-10H,11-12H2,1-2H3,(H,21,22)(H,23,24)

2-[4-[2-[(4-chlorobenzoyl)amino]ethyl]phenoxy]-2-methyl-propanoic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.91 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.91 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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配方 3 中的溶解度: 10 mg/mL (27.64 mM) in 0.5% CMC-Na/saline water (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。