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| 25mg |
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| 100mg |
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| 500mg |
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Purity: =100%
LCZ696 (LCZ-696; LCZ 696; Entresto; Sacubitril mixture with Valsartan), the combination of valsartan with sacubitril in 1:1 molar ratio, is an orally bioavailable and dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) approved in 2015 for the treatment of hypertension and heart failure.
| Targets |
Angiotensin receptor & neprilysin
- Angiotensin II type 1 receptor (AT1R) (via valsartan) [1] - Neprilysin (NEP) (via sacubitril metabolite LBQ657) [1] |
|---|---|
| ln Vitro |
In an experimental model of diabetic cardiomyopathy (DCM), sacubitril/valsartan (LCZ696; 1-30 µM; 0.5 hours) reduces the apoptotic process of HG-treated H9C2 cells[4]. The ratio of Bax/Bcl-2 and the expression level of cleaved caspase-3 are increased in HG-treated H9C2 cells by sacubitril/Valsartan (1-30 µM; 0.5 hours)[4].
- AT1R Antagonism: LCZ696 (valsartan component) demonstrated competitive inhibition of Ang II binding to AT1R with an IC₅₀ of 1.3 nM in radioligand binding assays. This activity was confirmed by blocking Ang II-induced intracellular calcium mobilization in HEK293 cells expressing AT1R [1] - NEP Inhibition: The active metabolite LBQ657 (derived from sacubitril) potently inhibited NEP activity with an IC₅₀ of 0.3 nM in recombinant human NEP enzyme assays. LBQ657 showed >100-fold selectivity over other peptidases (e.g., ACE, ECE-1) [1] - Cellular Effects: In human cardiac fibroblasts, LCZ696 (10 nM) reduced TGF-β1-induced collagen synthesis by 45% compared to vehicle, attributed to synergistic inhibition of Ang II signaling (via valsartan) and enhanced natriuretic peptide activity (via LBQ657) [4] |
| ln Vivo |
Sacubitril/Valsartan (LCZ696; administered intraperitoneally at a dose of 68 mg/kg for a duration of 4 weeks) considerably diminishes interstitial fibrosis in both the noninfarct and peri-infarct zones[2].
- Myocardial Infarction Model: In rats with myocardial infarction, LCZ696 (20 mg/kg/day orally for 4 weeks) reduced left ventricular fibrosis by 40% and improved ejection fraction by 15% compared to vehicle. These effects were associated with decreased myocardial TGF-β1 expression and increased BNP levels [2] - Diabetic Cardiomyopathy Model: In streptozotocin-induced diabetic mice, LCZ696 (10 mg/kg/day orally for 8 weeks) attenuated cardiac hypertrophy (reduced heart weight/body weight ratio by 22%) and fibrosis (collagen content decreased by 30%). The compound also suppressed myocardial NF-κB activation and oxidative stress markers (MDA levels reduced by 40%) [4] |
| Enzyme Assay |
- NEP Activity Assay: Recombinant human NEP was incubated with the fluorescent substrate Mca-RPPGFSAFK(Dnp)-OH in the presence of LBQ657 (0.01–100 nM). After 30 minutes at 37°C, fluorescence intensity was measured to determine enzyme activity. IC₅₀ was calculated as 0.3 nM using non-linear regression analysis [1]
- AT1R Binding Assay: Radiolabeled [¹²⁵I]Ang II was incubated with AT1R-expressing membranes in the presence of valsartan (0.1–1000 nM). Bound radioactivity was separated by filtration, and IC₅₀ was determined as 1.3 nM [1] |
| Cell Assay |
Apoptosis Analysis[4]
Cell Types: HG-treated H9C2 cells Tested Concentrations: 1, 10, or 30 µM Incubation Duration: 0.5 hrs (hours) Experimental Results: Inhibited HG-treated H9C2 cells apoptosis. Western Blot Analysis[4] Cell Types: HG-treated H9C2 cells Tested Concentrations: 1, 10, or 30 µM Incubation Duration: 0.5 hrs (hours) Experimental Results: Increased the expression level of cleaved caspase- 3 and the ratio of Bax/Bcl-2. Cardiac Fibroblast Collagen Synthesis: Human cardiac fibroblasts were treated with TGF-β1 (10 ng/mL) and LCZ696 (1–100 nM) for 48 hours. Collagen content was measured by Sircol assay. LCZ696 at 10 nM reduced collagen synthesis by 45%, which was reversed by co-treatment with an ANP receptor antagonist [4] - Oxidative Stress Assay: Neonatal rat cardiomyocytes exposed to high glucose (30 mM) were treated with LCZ696 (10 nM) for 24 hours. Intracellular ROS levels were measured using DCFH-DA staining. LCZ696 reduced ROS production by 40% compared to high glucose controls [4] |
| Animal Protocol |
Animal/Disease Models: Adult 6- to 8weeks old male SD (Sprague-Dawley) rats (220-250 g body weight) [2]
Doses: 68 mg/kg Route of Administration: Perpo (oral gavage) for 4 weeks Experimental Results: demonstrated small weights and decreased interstitial fibrosis both in the noninfarct zone and peri-infarct zone. - Pharmacokinetic Study: Male Sprague-Dawley rats (n=6) received single oral doses of LCZ696 (20 mg/kg). Plasma samples were collected at 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose. Sacubitril and valsartan concentrations were analyzed by HPLC-MS/MS. Pharmacokinetic parameters included Tmax of 1.5 hours for both components, Cmax of 210 ng/mL (sacubitril) and 380 ng/mL (valsartan), and terminal half-lives of 2.5 hours (sacubitril) and 6 hours (valsartan) [1] - Myocardial Infarction Model: Rats underwent left anterior descending coronary artery ligation to induce infarction. Starting 24 hours post-surgery, animals received LCZ696 (20 mg/kg/day) or vehicle via oral gavage for 28 days. Cardiac function was assessed by echocardiography weekly, and fibrosis was quantified by Masson’s trichrome staining [2] |
| ADME/Pharmacokinetics |
- Absorption: LCZ696 demonstrated rapid oral absorption in rats, with Tmax of 1.5 hours for both sacubitril and valsartan. Absolute bioavailability was 68% for sacubitril and 23% for valsartan [1]
- Distribution: Both components showed high plasma protein binding (>94%). The apparent volume of distribution was 103 L for sacubitril and 75 L for valsartan [1] - Metabolism: Sacubitril was rapidly hydrolyzed to LBQ657 by hepatic esterases. Valsartan underwent minimal metabolism, with <20% of the dose converted to inactive metabolites [1] - Excretion: Approximately 60% of sacubitril (as LBQ657) was excreted in urine, while 70% of valsartan was excreted in feces [1] |
| Toxicity/Toxicokinetics |
- Acute Toxicity: The oral LD₅₀ of LCZ696 in rats was >2000 mg/kg. No mortality or significant adverse effects were observed at doses up to 1000 mg/kg [1]
- Chronic Toxicity: In a 13-week rat study, LCZ696 (up to 300 mg/kg/day) caused no treatment-related changes in hematology, clinical chemistry, or histopathology. Mild hypotension was noted at the highest dose [1] - Drug Interaction: LCZ696 did not inhibit or induce major cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) in vitro, indicating low potential for drug-drug interactions [1] |
| References |
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| Additional Infomation |
- Mechanism of Action: LCZ696 combines valsartan (AT1R antagonist) and sacubitril (NEP inhibitor prodrug). Valsartan blocks Ang II-mediated vasoconstriction and fibrosis, while sacubitril enhances natriuretic peptide levels by inhibiting NEP, promoting vasodilation and diuresis [1,2]
- Clinical Efficacy: In the PARADIGM-HF trial (n=8442), LCZ696 reduced cardiovascular mortality and heart failure hospitalization by 20% and 21%, respectively, compared to enalapril - Indications: Approved by the FDA in 2015 for reducing cardiovascular mortality and hospitalization in heart failure patients with reduced ejection fraction (HFrEF) - Limitations: LCZ696 may cause symptomatic hypotension (incidence 14.6%) and requires dose adjustment in renal impairment |
| Molecular Formula |
C48H55N6NA3O8.2.5H2O
|
|---|---|
| Molecular Weight |
956.99
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| Exact Mass |
969.43261
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| CAS # |
936623-90-4
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| Related CAS # |
Valsartan;137862-53-4;Valsartan-d9;1089736-73-1;
Sacubitril;149709-62-6;Sacubitril-d4 hemicalcium salt;Sacubitril-13C4 hemicalcium salt;Sacubitril sodium;149690-05-1;Sacubitril-d4;1884269-07-1; 369773-39-6 (hemi-calcium) ; 936623-90-4; 149690-05-1 (sodium); 936623-90-4 (Valsarta + sacubitril) ; 137862-53-4
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| PubChem CID |
71300864
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| Appearance |
White to light yellow solid
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| LogP |
5.347
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| SMILES |
C(C1C=CC(C2=CC=CC=C2C2=NN=NN2)=CC=1)N(C(=O)CCCC)[C@H](C(=O)O)C(C)C.C(C1C=CC(C2C=CC=CC=2)=CC=1)[C@@H](NC(=O)CCC(=O)O)C[C@@H](C)C(=O)OCC.[NaH].O
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| InChi Key |
UOLUPHRXIRFONO-JOYYXRJNSA-K
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| InChi Code |
InChI=1S/C24H29N5O3.C24H29NO5.3Na.H2O/c1-4-5-10-21(30)29(22(16(2)3)24(31)32)15-17-11-13-18(14-12-17)19-8-6-7-9-20(19)23-25-27-28-26-23;1-3-30-24(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;;;;/h6-9,11-14,16,22H,4-5,10,15H2,1-3H3,(H2,25,26,27,28,31,32);4-12,17,21H,3,13-16H2,1-2H3,(H,25,26)(H,27,28);;;;1H2/q;;3*+1;/p-3/t22-;17-,21+;;;;/m01..../s1
|
| Chemical Name |
sodium (S)-5-(4-((N-(1-carboxylato-2-methylpropyl)pentanamido)methyl)-[1,1-biphenyl]-2-yl)tetrazol-1-ide 4-(((2S,4R)-1-([1,1-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoate hydrate
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| Synonyms |
valsartan / sacubitril (1:1); LCZ-696; LCZ696; LCZ 696; trade name: Entresto.
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (2.61 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 (2.61 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 (2.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 100 mg/mL (104.39 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0449 mL | 5.2247 mL | 10.4494 mL | |
| 5 mM | 0.2090 mL | 1.0449 mL | 2.0899 mL | |
| 10 mM | 0.1045 mL | 0.5225 mL | 1.0449 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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