| Size | Price | Stock | Qty |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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Purity: ≥98%
Sacubitrilat (formerly known as LBQ-657; LBQ657) is the activated form of Sacubitril (AHU-377; AHU-377; Entresto), which is a novel and potent NEP (neutral endopeptidase 24.11) inhibitor used in combination with valsartan (LCZ696) for treating heart failure. Sacubitril is a prodrug that requires esterases to de-ethylate in order to be converted into the active form LBQ657. Atrial and brain natriuretic peptides are two peptides that lower blood pressure primarily by decreasing blood volume. LBQ657 inhibits the enzyme neprilysin, which is in charge of breaking these peptides down.
| Targets |
NEP
|
|---|---|
| ln Vitro |
Sacubitrilat (LBQ657) has a distinct stereocenter and is a single diastereomer. Sacubitrilat exhibits a high inhibitory efficacy of 5 nM upon binding to the active site of NEP via a complicated response network including all of the compound's functional groups [1].
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| ln Vivo |
The present study summarizes the pharmacokinetics of sacubitrilat, sacubitrilat la (LBQ657), and the insecticide Sartan after a single sidewall dose of LCZ696 at 400 or 1200 mg during fasting. With a median Tmax of 0.52 h for the 400 mg dose and 1.05 h for the 1200 mg dose, Sacubitril's mean intraperitoneal concentration rose quickly. Sacubitril was next, with corresponding Tmax values of 2.07 and 3.05 h, respectively. The median brasartan Tmax for the 400 mg and 1200 mg dosages of LCZ696 was 2.07 hours. Sacubitril's Cmax shown a dose-proportional increase, while the Cmaxes of both Sacubitril and Sacubitril demonstrated an increase that was not proportionate to the dosages. Arithmetic tools AUC0-24 h and AUClast exhibited less of a dose-proportional increase for Sartan, but increased about dose-proportionally for Sacubitril and Sacubitrilat [2].
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| Enzyme Assay |
Sacubitril is an ethyl ester prodrug of LBQ657, the active neprilysin (NEP) inhibitor, and a component of LCZ696 (sacubitril/valsartan). We report herein the three-dimensional structure of LBQ657 in complex with human NEP at 2 Å resolution. The crystal structure unravels the binding mode of the compound occupying the S1, S1' and S2' sub-pockets of the active site, consistent with a competitive inhibition mode. An induced fit conformational change upon binding of the P1'-biphenyl moiety of the inhibitor suggests an explanation for its selectivity against structurally homologous zinc metallopeptidases [1].
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| Animal Protocol |
Purpose: Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA class II-IV) and reduced ejection fraction. This study was aimed to evaluate the effect of single oral therapeutic (400 mg) and supratherapeutic (1200 mg) doses of LCZ696 on cardiac repolarization.[2]
Method: This randomized double-blind crossover study in healthy male subjects compared the effect of therapeutic and supratherapeutic doses of LCZ696 with placebo and moxifloxacin 400 mg (open-label treatment) as positive control. The primary assessment was mean baseline- and placebo-corrected QTcF (∆∆QTcF; Fridericia correction). Additional assessments included the ∆∆QTcB (Bazett's correction), PR interval, QRS duration, heart rate (HR), LCZ696 pharmacokinetics, pharmacokinetic/pharmacodynamic relationships, and safety.[2] Results: Of the 84 subjects enrolled, 81 completed the study. The maximum upper bound of the two-sided 90 % confidence interval for ∆∆QTcF for LCZ696 400 mg and 1200 mg were <10 ms, and assay sensitivity was confirmed with moxifloxacin. No relevant treatment-emergent changes were observed in any of the ECG-derived parameters with LCZ696 or placebo, and the incidence of adverse events was comparable among the treatment groups.[2] |
| References | |
| Additional Infomation |
A metabolite of LCZ696 with neprilysin inhibitory activity.
Sacubitrilat is a Neprilysin Inhibitor. The mechanism of action of sacubitrilat is as a Neprilysin Inhibitor. |
| Molecular Formula |
C22H25NO5
|
|---|---|
| Molecular Weight |
383.4376
|
| Exact Mass |
383.173
|
| Elemental Analysis |
C, 68.91; H, 6.57; N, 3.65; O, 20.86
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| CAS # |
149709-44-4
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| Related CAS # |
Sacubitrilat-d4
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| PubChem CID |
10430040
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| Appearance |
White to off-white solid powder
|
| LogP |
4.196
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| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
10
|
| Heavy Atom Count |
28
|
| Complexity |
521
|
| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@H](C[C@@H](CC1=CC=C(C=C1)C2=CC=CC=C2)NC(=O)CCC(=O)O)C(=O)O
|
| InChi Key |
DOBNVUFHFMVMDB-BEFAXECRSA-N
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| InChi Code |
InChI=1S/C22H25NO5/c1-15(22(27)28)13-19(23-20(24)11-12-21(25)26)14-16-7-9-18(10-8-16)17-5-3-2-4-6-17/h2-10,15,19H,11-14H2,1H3,(H,23,24)(H,25,26)(H,27,28)/t15-,19+/m1/s1
|
| Chemical Name |
(2R,4S)-4-(3-carboxypropanoylamino)-2-methyl-5-(4-phenylphenyl)pentanoic acid
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| Synonyms |
Sacubitrilat; LBQ657; LBQ-657; LBQ 657
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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)
|
| Solubility (In Vitro) |
DMSO: ~77 mg/mL (~200.8 mM)
Ethanol: ~77 mg/mL (~200.8 mM) |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.52 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 (6.52 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 (6.52 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 | 2.6080 mL | 13.0398 mL | 26.0797 mL | |
| 5 mM | 0.5216 mL | 2.6080 mL | 5.2159 mL | |
| 10 mM | 0.2608 mL | 1.3040 mL | 2.6080 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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