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| Targets |
Ezetimibe D4 targets the Niemann-Pick C1-like1 (NPC1L1) protein, which is a cholesterol transporter located on the brush border membrane of enterocytes in the small intestine. By binding to NPC1L1, ezetimibe blocks the uptake of dietary and biliary cholesterol from the intestinal lumen, reducing the amount of cholesterol that is absorbed into the bloodstream. This mechanism of action is distinct from that of statins, which inhibit cholesterol synthesis in the liver. In addition to its effects on NPC1L1, ezetimibe is also a potent activator of the Nrf2 pathway, which regulates the expression of antioxidant and detoxification enzymes. The deuterium atoms in Ezetimibe D4 do not alter the compound's binding affinity or pharmacological activity, as the isotope substitution does not significantly affect the compound's three-dimensional structure or its interactions with molecular targets. The compound's dual mechanism of action makes it a valuable tool for studying cholesterol metabolism and oxidative stress.
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| ln Vitro |
In vitro studies on Ezetimibe D4 are limited, as the compound is primarily used as an internal standard rather than as a pharmacological tool. However, the parent compound ezetimibe has been extensively characterized in vitro. Ezetimibe inhibits NPC1L1-mediated cholesterol uptake in enterocyte models with high potency, with IC₅₀ values in the nanomolar range. The compound also activates Nrf2 in various cell types, leading to the upregulation of antioxidant enzymes such as HO-1, NQO1, and GST. In cancer cell lines, ezetimibe has been shown to inhibit cell proliferation and induce apoptosis, although these effects are likely related to its Nrf2-activating properties rather than its cholesterol-lowering effects. Ezetimibe D4 exhibits identical chromatographic and mass spectrometric behavior to ezetimibe but can be distinguished by mass due to the 4 Da mass shift, making it an ideal internal standard for analytical methods.
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| ln Vivo |
In vivo studies on Ezetimibe D4 are not typically performed, as the compound is used as an analytical standard rather than as a therapeutic agent. However, the pharmacokinetics and pharmacodynamics of the parent compound ezetimibe have been extensively studied in humans and animals. Ezetimibe reduces plasma LDL cholesterol levels by approximately 15-20% when administered as monotherapy and by an additional 20-25% when used in combination with statins. The compound is well-tolerated and has a favorable safety profile. Ezetimibe D4 can be used in pharmacokinetic studies to quantify ezetimibe levels in plasma, tissues, and other biological matrices, enabling the accurate assessment of drug exposure and the evaluation of drug-drug interactions.
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| Enzyme Assay |
For in vitro analytical applications, Ezetimibe D4 is used as an internal standard for the quantification of ezetimibe in biological samples by LC-MS or GC-MS. A typical protocol involves the addition of a known amount of Ezetimibe D4 to the sample (plasma, urine, tissue homogenate) prior to sample preparation. The sample is then extracted using liquid-liquid extraction (LLE) or solid-phase extraction (SPE), and the extract is analyzed by LC-MS/MS using a reversed-phase column and a mobile phase consisting of acetonitrile and water with formic acid or ammonium acetate. The mass spectrometer is operated in positive ion mode, and the transition for ezetimibe (m/z 410.2 → 272.1) and for Ezetimibe D4 (m/z 414.2 → 276.1) is monitored. The concentration of ezetimibe in the sample is calculated from the peak area ratio of ezetimibe to Ezetimibe D4 using a calibration curve prepared with known concentrations of ezetimibe and a fixed concentration of Ezetimibe D4. The method is validated for linearity, accuracy, precision, and recovery according to regulatory guidelines.
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| Cell Assay |
For in vitro cell-based assays, Ezetimibe D4 is not typically used, as its primary application is as an analytical standard. However, if used, it would be expected to exhibit the same biological activity as ezetimibe. Cells (e.g., Caco-2 enterocytes, HepG2 hepatocytes) are seeded in 6- or 12-well plates and treated with ezetimibe or Ezetimibe D4 at concentrations of 0.01-10 µM for 24-48 hours. Cholesterol uptake is measured using radiolabeled cholesterol or fluorescent cholesterol analogs. Nrf2 activation is assessed by measuring the expression of Nrf2 target genes (HO-1, NQO1) by qPCR or by using an ARE-luciferase reporter assay. Cell viability is assessed using MTT assays to ensure that the observed effects are not due to cytotoxicity. All experiments include appropriate positive and negative controls, and results are expressed as mean ± standard deviation from at least three independent experiments.
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| Animal Protocol |
For in vivo animal experiments, Ezetimibe D4 is not typically administered to animals as a therapeutic agent. However, the compound can be used in pharmacokinetic studies to measure ezetimibe levels in animal models. In a typical study, animals (e.g., rats, mice, dogs) are administered ezetimibe orally at doses of 0.1-10 mg/kg. Blood samples are collected at various time points (0, 0.5, 1, 2, 4, 6, 8, 12, 24 hours), and plasma is separated by centrifugation. Ezetimibe D4 is added to the plasma samples as an internal standard, and the samples are extracted and analyzed by LC-MS/MS. Pharmacokinetic parameters, including Cmax, Tmax, AUC, t½, and oral bioavailability, are calculated using non-compartmental analysis. For tissue distribution studies, animals are euthanized at various time points, and tissues (liver, kidney, intestine, adipose) are collected, homogenized, and analyzed for ezetimibe content using Ezetimibe D4 as an internal standard. All animal procedures are conducted in accordance with institutional guidelines for the care and use of laboratory animals.
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| ADME/Pharmacokinetics |
Ezetimibe D4 is intended for use as an internal standard and is not used as a therapeutic agent. The compound has a molecular weight of 413.45 g/mol and a molecular formula of C₂₄H₂₁F₂NO₃ (with four deuterium atoms). It is stable when stored as a powder at -20°C for up to 3 years and in solution at -80°C for up to 2 years. The compound is soluble in DMSO, methanol, and other organic solvents. Ezetimibe D4 is available from various research chemical suppliers with high isotopic purity (>98%) and chemical purity (>95%).
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| Additional Infomation |
Ezetimibe D4 is a research-use only compound and has not been approved for clinical applications as a deuterated drug. It is also known as SCH 58235 D4. The compound has a molecular formula of C₂₄H₂₁F₂NO₃ and a molecular weight of 413.45 g/mol. Ezetimibe D4 is the deuterium-labeled version of ezetimibe, a potent, selective cholesterol absorption inhibitor that targets NPC1L1 and activates Nrf2. The compound is intended for use as an internal standard for the quantification of ezetimibe by GC- or LC-MS in pharmacokinetic and bioanalytical studies. Ezetimibe D4 is available from various research chemical suppliers and is used in analytical chemistry, pharmaceutical research, and clinical pharmacology. Storage recommendations include keeping the compound in a tightly sealed container, protected from light and moisture, at -20°C.
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| Molecular Formula |
C₂₄H₁₇D₄F₂NO₃
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| Molecular Weight |
413.45
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| Exact Mass |
413.174
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| CAS # |
1093659-90-5
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| Related CAS # |
Ezetimibe;163222-33-1
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| PubChem CID |
25145350
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
654.9±55.0 °C at 760 mmHg
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| Melting Point |
152-154°C
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| Flash Point |
349.9±31.5 °C
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| Vapour Pressure |
0.0±2.1 mmHg at 25°C
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| Index of Refraction |
1.624
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| LogP |
3.26
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
30
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| Complexity |
567
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| Defined Atom Stereocenter Count |
3
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| SMILES |
[2H]C1=C(C(=C(C(=C1N2[C@@H]([C@H](C2=O)CC[C@@H](C3=CC=C(C=C3)F)O)C4=CC=C(C=C4)O)[2H])[2H])F)[2H]
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| InChi Key |
OLNTVTPDXPETLC-ARVCERDTSA-N
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| 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/i7D,8D,9D,10D
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| Chemical Name |
(3R,4S)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-1-(2,3,5,6-tetradeuterio-4-fluorophenyl)azetidin-2-one
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| Synonyms |
SCH 58235 D4SCH-58235 D4
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4187 mL | 12.0934 mL | 24.1867 mL | |
| 5 mM | 0.4837 mL | 2.4187 mL | 4.8373 mL | |
| 10 mM | 0.2419 mL | 1.2093 mL | 2.4187 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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