Ezetimibe (SCH 58235)

Alias: SCH-58235; SCH 58235; SCH-58235; SCH58235; trade names: Zetia, Ezetrol
Cat No.:V1878 Purity: ≥98%
Ezetimibe (also known as SCH-58235)is a potent and selective inhibitor of cholesterol absorption in the gut used to lower cholesterol levels.
Ezetimibe (SCH 58235) Chemical Structure CAS No.: 163222-33-1
Product category: Keap1-Nrf2
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Ezetimibe (also known as SCH-58235) is a potent and selective inhibitor of cholesterol absorption in the gut used to lower cholesterol levels. It functions by directly interfering with Niemann-Pick C1-like 1 (NPC1L1), preventing it from integrating into clathrin-coated vesicles. It is possible to absorb cholesterol through clathrin/AP2-mediated endocytosis thanks to the polytopic transmembrane protein NPC1L1. Ezetimibe inhibits cholesterol transfer across membranes by binding to NPC1L1 and preventing this protein's endocytosis. Clinical trials have shown that ezetimibe can reduce plasma cholesterol levels.

Biological Activity I Assay Protocols (From Reference)
Targets
NPC1L1; Nrf2
ln Vitro
Ezetimibe results in a small but significant increase in HDL cholesterol as well as a significant decrease in triglycerides, LDL cholesterol, and total cholesterol. [1] In Caco-2 cells, ezetimibe decreases cholesterol transport by 31% but does not affect retinol transport. As determined by real-time PCR analysis in Caco-2 cells, ezetimibe significantly reduces the mRNA expression of the nuclear and surface receptors retinoid acid receptor (RAR)gamma, sterol-regulatory element binding proteins (SREBP)-1 and -2, and liver X receptor (LXR)beta. [2]
ln Vivo
Ezetimibe lowers plasma cholesterol levels in mice on a western, low-fat, and cholesterol-free diet from 964 to 374 mg/dL, 726 to 231 mg/dL, and 516 to 178 mg/dL, respectively. Ezetimibe reduces the surface area of aortic atherosclerotic lesions from 20.2% to 4.1% in the group eating a western diet and from 24.1% to 7.0% in the mice eating a low-fat cholesterol diet. Ezetimibe decreases the cross-sectional area of carotid artery atherosclerotic lesions by 97% in the western and low-fat cholesterol groups and by 91% in mice lacking in cholesterol. Under western, low-fat, and cholesterol-free dietary conditions, ezetimibe inhibits cholesterol absorption, lowers plasma cholesterol, raises high density lipoprotein levels, and slows the development of atherosclerosis in apoE-/- mice.[3] Ezetimibe significantly lowers plasma cholesterol in preclinical animal models of hypercholesterolemia by potently inhibiting the transport of cholesterol across the intestinal wall. The rat model has shown that ezetimibe maintains bile flow while eliminating exocrine pancreatic function from the intestine. [4] With an ED(50) of 0.04 mg/kg, ezetimibe lowers plasma cholesterol and hepatic cholesterol buildup in hamsters receiving cholesterol-filled diets. [5]
Enzyme Assay
Escherichia coli is used to produce GST-p62, and 0.5 μg of the purified protein is used in an in vitro AMPK phosphorylation assay. A non-radioisotope method using S-ATP is used to determine the phosphorylation of the p62 protein by AMPK. AMPK complex is immuno-purified from HEK293 cells, and then Flag-AMPKβ1 and HA-AMPKγ1 are transfected into either myc-AMPKα1 wild-type (WT) or myc-AMPKα1 kinase-dead mutant (KD, D157A) cells. The reaction mixture contains 20 mM HEPES, pH 7.4, 1 mM EGTA, 0.4 mM EDTA, 5 mM MgCl2, 0.05 mM DTT, 0.5 μg GST-p62, 0.2 mM AMP, and 1 mM ATPS. AMPK complex is then added to the mixture. 30 minutes are spent conducting the reaction at 37°C, followed by the addition of 20 mM EDTA to end it. The reaction product is alkylated with 2.5 mM PNBM for 2 hours at room temperature in order to detect p62 protein that has been γS-labeled with an S-atom [1] before being analyzed by western blotting with an anti-thiophosphate antibody.
Cell Assay
Huh7 human hepatocytes are cultured at 37°C in a 95% air/5% CO2 environment using high glucose DMEM containing 10% FBS, 100 units/mL penicillin, and 100 g/mL streptomycin. Ezetimibe (10 μM, 1 h) and palmitic acid (0.5 mM, 24 h) are administered to hepatocytes with or without treatment[2].
Animal Protocol
Mice: We use male C57BL/6J mice that are ten weeks old. The three groups—normal chow diet, MCD diet with a vehicle treatment, or MCD diet with ezetimibe treatment—each containing 7–10 mice, are randomly chosen for the animals. The temperature was kept at 23±2°C, the humidity at 60%±10%, and there were 12-hour cycles of light and darkness for the mice. Ezetimibe 10 mg/kg is administered once daily by oral gavage to the MCD diet group for a period of four weeks. The same quantity of phosphate buffered saline was given orally to the chow and MCD diet with vehicle groups for a period of four weeks. Over the course of the therapy, weight is assessed once per week. The mice are sedated and killed after four weeks, and blood is extracted through a heart puncture. After being harvested, tissues are either fixed in formalin and then embedded in paraffin, or they are instantly frozen in liquid nitrogen and kept at -70°C.
Rats: The experiments are carried out in a particular pathogen-free facility with a 12 h light/dark cycle, using male OLETF (n=11) and age-matched LETO (n=3) rats. The OLETF rat is a model that depicts late-onset hyperglycemia and displays a chronic disease course, mild obesity, and clinical onset of diabetes mellitus. Animals have unrestricted access to food and water. Rats are randomized at 12 weeks of age and given either PBS or Ezetimibe (10 mg/kg per day) by stomach gavage for 20 weeks. The rats are fasted for the duration of the study, and then intraperitoneal Zoletil/Rompun is administered to put them to sleep. The liver is dissected, its tissues are immediately frozen in liquid nitrogen, and it is then stored at -80°C for later analysis after blood is drawn from the abdominal aorta.
References

[1]. Ezetimibe, an NPC1L1 inhibitor, is a potent Nrf2 activator that protects mice from diet-induced nonalcoholic steatohepatitis. Free Radic Biol Med. 2016 Sep 12;99:520-532.

[2]. Ezetimibe improves hepatic steatosis in relation to autophagy in obese and diabetic rats. World J Gastroenterol. 2015 Jul 7;21(25):7754-63.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C24H21F2NO3
Molecular Weight
409.4
Exact Mass
409.15
Elemental Analysis
C, 70.41; H, 5.17; F, 9.28; N, 3.42; O, 11.72
CAS #
163222-33-1
Appearance
Solid powder
SMILES
C1=CC(=CC=C1[C@@H]2[C@H](C(=O)N2C3=CC=C(C=C3)F)CC[C@@H](C4=CC=C(C=C4)F)O)O
InChi Key
OLNTVTPDXPETLC-XPWALMASSA-N
InChi Code
InChI=1S/C24H21F2NO3/c25-17-5-1-15(2-6-17)22(29)14-13-21-23(16-3-11-20(28)12-4-16)27(24(21)30)19-9-7-18(26)8-10-19/h1-12,21-23,28-29H,13-14H2/t21-,22+,23-/m1/s1
Chemical Name
(3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one
Synonyms
SCH-58235; SCH 58235; SCH-58235; SCH58235; trade names: Zetia, Ezetrol
HS Tariff Code
2934.99.9001
Storage

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ~82 mg/mL (~200.3 mM)
Water: <1 mg/mL
Ethanol: ~82 mg/mL (~200.3 mM)
Solubility (In Vivo)
2%DMSO+30%PEG 300+5%Tween 80+ddH2O: 10mg/mL
 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.4426 mL 12.2130 mL 24.4260 mL
5 mM 0.4885 mL 2.4426 mL 4.8852 mL
10 mM 0.2443 mL 1.2213 mL 2.4426 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.

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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT00033345 Active
Recruiting
Drug: Ezetimibe 10mg
Drug: Placebo
Diabetes Mellitus, Type 2
Diabetic Kidney Disease
Steno Diabetes Center
Copenhagen
October 1, 2020 Phase 3
NCT03355027 Active
Recruiting
Drug: Simvastatin 80mg
Drug: Rosuvastatin 40Mg
Tablet
Atherosclerosis
Cardiovascular Diseases
Cambridge University Hospitals
NHS Foundation Trust
November 30, 2017 Not Applicable
NCT04701242 Recruiting Drug: Ezetimibe 10mg Dyslipidemias
Acute Myocardial Infarction
Cairo University March 24, 2021 Not Applicable
NCT05763875 Recruiting Drug: Inclisiran
Drug: Ezetimibe
Hypercholesterolemia Novartis Pharmaceuticals March 15, 2023 Phase 3
NCT05974345 Not yet recruiting Drug: Placebo
Drug: Ezetimibe
Atherosclerotic Cardiovascular
Disease
Novartis Pharmaceuticals October 17, 2023
Biological Data
  • Ezetimibe improves hepatic steatosis in OLETF rats. World J Gastroenterol . 2015 Jul 7;21(25):7754-63.
  • Ezetimibe increases autophagy makers in OLETF liver tissue. World J Gastroenterol . 2015 Jul 7;21(25):7754-63.
  • Ezetimibe treatment attenuates triglycerides accumulation and induces autophagy in hepatocytes. World J Gastroenterol . 2015 Jul 7;21(25):7754-63.
  • Ezetimibe increases autophagosome formation and autophagic flux in hepatocytes. World J Gastroenterol . 2015 Jul 7;21(25):7754-63.
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