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2R,4S-Sacubitril is an impurity of Sacubitril (AHU-377; AHU377), which is an FDA approved medication used in combination with valsartan (trade name Entrosto for the combo/cocktail)for the treatment of heart failure.
| Targets |
Impurity of Sacubitril
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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].
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| References | |
| Additional Infomation |
最近，美国食品药品监督管理局批准沙库比曲与缬沙坦联合用于治疗射血分数降低的心力衰竭患者。作为前药，沙库必曲必须代谢（水解）为其活性代谢产物沙库必曲特（LBQ657）才能发挥其预期的治疗作用。因此，了解sacubitril激活的决定因素将有助于sacubitri药物治疗的改进。本研究的目的是确定负责sacubitril激活的酶，并确定遗传变异对sacubitri激活的影响。首先，对sacubitril与人血浆和人肝、肠和肾的S9级分进行了孵育研究。发现只有人肝S9级分才能激活萨克比曲。此外，羧酸酯酶1（CES1）抑制剂双-（对硝基苯基）磷酸酯在人肝脏S9中显著抑制了沙库必曲的激活。用重组人CES1和羧酸酯酶2进行的进一步孵育研究证实，沙库必曲是一种选择性的CES1底物。用野生型CES1和CES1变体G143E（rs71647871）转染的细胞系的体外研究表明，G143E是sacubitril激活的功能缺失变体。重要的是，在携带G143E变体的人类肝脏中，sacubitril的激活显著受损。总之，在人类肝脏中，sacubitril被CES1选择性激活。CES1基因变体G143E可显著损害sacubitril的激活。因此，CES1基因变异似乎是导致沙库必曲激活个体间变异的重要因素，并有可能作为优化沙库必曲药疗的生物标志物[1]。
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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 # |
761373-05-1
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| Related CAS # |
Sacubitril;149709-62-6
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| PubChem CID |
9978992
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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@@H](C)C[C@H](CC1C=CC(C2C=CC=CC=2)=CC=1)NC(CCC(=O)O)=O)=O
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| InChi Key |
PYNXFZCZUAOOQC-LAUBAEHRSA-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+/m0/s1
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| Chemical Name |
4-[[(2R,4S)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid
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| Synonyms |
761373-05-1; 2R,4S-Sacubitril; (2R,4S)-5-(Biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoic acid ethyl ester; (2S,4R)-Sacubitril; 4-[[(2R,4S)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoic acid; ahu377 isomer 2; 4-(((2R,4S)-1-([1,1'-Biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid; SCHEMBL22420467;
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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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