| Size | Price | Stock | Qty |
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| 2mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
Impurity of Sacubitril
2R,4R-Sacubitril targets neprilysin (NEP), an enzyme that breaks down natriuretic peptides. By inhibiting NEP, it increases the levels of natriuretic peptides, promoting vasodilation and reducing blood pressure. It is used as an impurity standard in analytical method development and quality control for sacubitril-containing products. |
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| ln Vitro |
Sacubitril was recently approved by the Food and Drug Administration for use in combination with valsartan for the treatment of patients with heart failure with reduced ejection fraction. As a prodrug, sacubitril must be metabolized (hydrolyzed) to its active metabolite sacubitrilat (LBQ657) to exert its intended therapeutic effects. Thus, understanding the determinants of sacubitril activation will lead to the improvement of sacubitril pharmacotherapy. The objective of this study was to identify the enzyme(s) responsible for the activation of sacubitril, and determine the impact of genetic variation on sacubitril activation. First, an incubation study of sacubitril with human plasma and the S9 fractions of human liver, intestine, and kidney was conducted. Sacubitril was found to be activated by human liver S9 fractions only. Moreover, sacubitril activation was significantly inhibited by the carboxylesterase 1 (CES1) inhibitor bis-(p-nitrophenyl) phosphate in human liver S9. Further incubation studies with recombinant human CES1 and carboxylesterase 2 confirmed that sacubitril is a selective CES1 substrate. The in vitro study of cell lines transfected with wild-type CES1 and the CES1 variant G143E (rs71647871) demonstrated that G143E is a loss-of-function variant for sacubitril activation. Importantly, sacubitril activation was significantly impaired in human livers carrying the G143E variant. In conclusion, sacubitril is selectively activated by CES1 in human liver. The CES1 genetic variant G143E can significantly impair sacubitril activation. Therefore, CES1 genetic variants appear to be an important contributing factor to interindividual variability in sacubitril activation, and have the potential to serve as biomarkers to optimize sacubitril pharmacotherapy[1].
In vitro, 2R,4R-Sacubitril is used as a reference standard and impurity for analytical method development. Its activity as a neprilysin inhibitor is expected to be similar to that of sacubitril, but its potency may differ due to the stereochemical configuration. |
| ln Vivo |
In vivo, 2R,4R-Sacubitril is not administered as a therapeutic agent. As an impurity of sacubitril, its presence in pharmaceutical products is controlled to ensure product quality and safety.
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| Enzyme Assay |
In vitro assays for 2R,4R-Sacubitril are primarily analytical in nature. High-performance liquid chromatography (HPLC) or ultra-performance liquid chromatography (UPLC) with UV detection is used to quantify the impurity in sacubitril drug substance and drug products. Mass spectrometry (LC-MS/MS) may also be used for identification and quantification.
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| Cell Assay |
Cellular assays for 2R,4R-Sacubitril are not typically performed, as it is an impurity rather than an active pharmaceutical ingredient. Its effects on neprilysin activity could be assessed in cell-based assays if needed.
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| Animal Protocol |
In vivo animal studies for 2R,4R-Sacubitril are not typically conducted, as it is an impurity rather than an active pharmaceutical ingredient. Studies would focus on toxicological assessment of the impurity in the context of sacubitril safety evaluation.
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| ADME/Pharmacokinetics |
Pharmacokinetic data for 2R,4R-Sacubitril are not available, as it is not administered as a therapeutic agent. Its PK properties would be expected to be similar to those of sacubitril if administered, but its presence in pharmaceutical preparations is typically at trace levels.
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| Toxicity/Toxicokinetics |
Toxicological data for 2R,4R-Sacubitril are limited. As an impurity of sacubitril, its toxicity is assessed as part of the overall safety evaluation of sacubitril drug products. At the trace levels present, it is not expected to contribute significantly to the toxicity profile.
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| References | |
| Additional Infomation |
2R,4R-Sacubitril is a stereoisomer and impurity of sacubitril, an FDA-approved neprilysin inhibitor used for heart failure. It has a molecular weight of 411.49 and formula C24H29NO5. It is used as a reference standard in analytical development and quality control for sacubitril pharmaceuticals. It is not a drug and has no clinical approval.
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| Molecular Formula |
C24H29NO5
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|---|---|
| Molecular Weight |
411.490767240524
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| Exact Mass |
411.204
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| CAS # |
766480-48-2
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| Related CAS # |
Sacubitril;149709-62-6
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| PubChem CID |
9829628
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| Appearance |
Colorless to light yellow ointment
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
656.9±55.0 °C at 760 mmHg
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| Flash Point |
351.1±31.5 °C
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| Vapour Pressure |
0.0±2.1 mmHg at 25°C
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| Index of Refraction |
1.549
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| LogP |
3.96
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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 |
12
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| Heavy Atom Count |
30
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| Complexity |
550
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| Defined Atom Stereocenter Count |
2
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| SMILES |
O(CC)C(C(C)CC(CC1C=CC(C2C=CC=CC=2)=CC=1)NC(CCC(=O)O)=O)=O
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| InChi Key |
PYNXFZCZUAOOQC-DYESRHJHSA-N
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| InChi Code |
InChI=1S/C24H29NO5/c1-3-30-24(29)17(2)15-21(25-22(26)13-14-23(27)28)16-18-9-11-20(12-10-18)19-7-5-4-6-8-19/h4-12,17,21H,3,13-16H2,1-2H3,(H,25,26)(H,27,28)/t17-,21-/m1/s1
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| Chemical Name |
4-[[(2R,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid
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| Synonyms |
2R,4R-Sacubitril; 766480-48-2; LCZ 696 Impurity B; (2R,4R)-Sacubitril; 4-((Rel-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid; 4-[[(2R,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid; (R*,R*)-?-[(3-Carboxy-1-oxopropyl)amino]-a-methyl-[1,1'-biphenyl]-4-pentanoic Acid a-Ethyl Ester; (aR,?R)-rel-?-[(3-Carboxy-1-oxopropyl)amino]-a-methyl-[1,1'-biphenyl]-4-pentanoic Acid 4-Ethyl Ester; Sacubitril-(2R,4R) Isomer;Impurity B; SCHEMBL18574632;
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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) |
DMSO : ~100 mg/mL (~243.02 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.08 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.08 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4302 mL | 12.1510 mL | 24.3019 mL | |
| 5 mM | 0.4860 mL | 2.4302 mL | 4.8604 mL | |
| 10 mM | 0.2430 mL | 1.2151 mL | 2.4302 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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