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

Bezafibrate is a PPAR agonist. For mouse PPARα, PPARγ, and PPARδ, the corresponding EC50 values are 90 μM, 55 μM, and 110 μM. Human PPARα, PPARγ, and PPARδ have respective EC50 values of 50 μM, 60 μM, and 20 μM. is [1]. When applied to human retinal pigment epithelial ARPE-19 cells and human retinal microvascular endothelial cells (HRMEC), bezafibrate (>200 μM) exhibits notable cytotoxicity. In HRMEC, bezafibrate (30-100 μM) reduces TNFα-induced inflammatory factors and controls TNFα-induced nuclear factor (NF)-κB transactivation. Bezafibrate inhibits the migration of HRMECs caused by VEGF and the release of VEGF by ARPE-19 cells stimulated by interleukin (IL)-1β [2].

In TallyHo mice, bezafibrate (0.5%) markedly decreased plasma lipid and glucose levels and increased the size of the pancreatic islet. Bezafibrate also enhances metabolic flexibility and energy expenditure. Bezafibrate also enhances steatosis, modifies the makeup of lipids, and boosts the mass of mitochondria in the liver [3].

Furthermore, bezafibrate is a fibrate drug commonly used as a lipid-lowering agent to treat hyperlipidemia and acts as a pan-agonist of all PPARs subtypes. However, the effects of bezafibrate in diabetic retinopathy remain unclear. Therefore, the purpose of this study was to investigate the effects of bezafibrate on retinal microvascular inflammation. Bezafibrate was not cytotoxic against human retinal microvascular endothelial cells (HRMECs) and human retinal pigment epithelial cells (ARPE-19 cells) treated with <100 and 200μM bezafibrate, respectively. In HRMECs, the expression levels of tumor necrosis factor (TNF)-α-induced monocyte chemoattractant protein (MCP)-1, intercellular adhesion molecule (ICAM)-1, and vascular cell adhesion molecule (VCAM)-1 were significantly suppressed by bezafibrate in a dose-dependent manner. TNF-α-induced nuclear translocation of nuclear factor (NF)-κB p65 and cell migration were also significantly inhibited in bezafibrate-treated HRMECs. Furthermore, bezafibrate treatment significantly suppressed interleukin (IL)-1β-induced vascular endothelial growth factor (VEGF) production in ARPE-19 cells. These results suggest that bezafibrate has beneficial effects on retinal microvascular inflammation. Our study demonstrates the therapeutic potential of bezafibrate for managing diabetic retinopathy[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

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)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.91 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.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.91 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly.

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Solubility in Formulation 3: 10 mg/mL (27.64 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)