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Purity: ≥98%
Sacubitril hemicalcium (also known as AHU377; AHU-377; Entresto) is a novel and potent NEP (neutral endopeptidase 24.11) inhibitor with an IC50 of 5 nM. It is a component of the heart failure medication LCZ696 (sacubitril/valsartan). This prodrug can be converted to LBQ657 by using esterases to de-ethylate it. The blood pressure-lowering peptides atrial and brain natriuretic peptide, which primarily lower blood volume, are broken down by the enzyme neprilysin, which is inhibited by LBQ657.
| Targets |
NEP (neprilysin) (IC50 = 5 nM)
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|---|---|
| ln Vitro |
Combining the molecular components of valsartan (an ARB) and sacubitril hemicalcium salt (a neprilysin inhibitor) in a 1:1 ratio, sacubitril (AHU-377) is a single molecule. Enzymatic cleavage of the ethyl ester converts sacubitril (AHU-377) to the active enkephalinase-inhibiting metabolite LBQ657 [2]. Sacubitril hemicalcium salt, an inactive NEPi precursor, does not prevent collagen from building up in fibroblasts or cardiomyocyte hypertrophy. There was no discernible impact of active NEPi LBQ657 on cardiac fibroblasts. By comparison, cardiomyocyte enlargement is moderately inhibited by LBQ657 [3].
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| ln Vivo |
Sacubitril (AHU-377) is absorbed quickly in humans (tmax 0.5-1.1 h). The fast conversion of sacubitril hemicalcium salt to LBQ657 results in a tmax in 1.9–3.5 hours. Biologically active LBQ657 has an average half-life of 9.9–11.1 hours [2]. ANF raised urine natriuresis in dogs treated with a vehicle from 17.3±3.6 to 199.5±18.4 pequivkglmin. The effects of sacubitril (AHU-377) were markedly amplified in the animals. Urine production is similarly increased in animals given intravenous Sacubitril (AHU-377) [1].
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| Cell Assay |
Cellular Cardiac Hypertrophy and Fibrosis In Vitro [3]
Rat neonatal cardiac myocytes and fibroblasts were obtained from 1- to 2-day-old Sprague–Dawley rat pups by enzymatic collagenase digestion and prepared for in vitro assays as routinely used in our laboratory.22 Cardiac myocyte hypertrophy was assessed by AngII-stimulated (100 nmol/L) neonatal cardiac myocytes with 3[H]leucine incorporation for 60 hours. AngII-stimulated (100 nmol/L) collagen synthesis was determined by 3[H]proline incorporation in neonatal cardiac fibroblasts for 48 hours. Cells were preincubated with valsartan, AHU377, LBQ657, or valsartan+LBQ657 (ARNi) for 1 hour before stimulation. Dose ranges used and NEPi to ARB ratios aimed to replicate as far as possible doses of LCZ696 used clinically. The drugs were a kind gift of Novartis, Basel, Switzerland. In addition, exogenous B-type natriuretic peptide (BNP) was added at different concentrations into the cell culture media just before AngII stimulation to assess the effect of direct augmentation of NP signaling. Experiments were repeated 2 to 4× in triplicate each time. |
| Animal Protocol |
One week after MI, adult male Sprague-Dawley rats were randomized to treatment for 4 weeks with LCZ696 (68 mg/kg body weight perorally; MI-ARNi, n=11) or vehicle (MI-vehicle, n=6). Five weeks after MI, MI-ARNi versus MI-vehicle demonstrated lower LV end-diastolic diameter (by echocardiography; 9.7±0.2 versus 10.5±0.3 mm), higher LV ejection fraction (60±2 versus 47±5%), diastolic wall strain (0.23±0.02 versus 0.13±0.02), and circular strain (-9.8±0.5 versus -7.3±0.5%; all P<0.05). LV pressure-volume loops confirmed improved LV function. Despite similar infarct size, MI-ARNi versus MI-vehicle had lower cardiac weights (P<0.01) and markedly reduced fibrosis in peri-infarct and remote myocardium. Angiotensin II-stimulated incorporation of 3[H]leucine in cardiac myocytes and 3[H]proline in cardiac fibroblast was used to evaluate hypertrophy and fibrosis, respectively. The neprilysin inhibitor component of LCZ696, LBQ657, inhibited hypertrophy but not fibrosis. The angiotensin receptor blocker component of LCZ696, valsartan inhibited both hypertrophy and fibrosis. Dual valsartan+LBQ augmented the inhibitory effects of valsartan and the highest doses completely abrogated angiotensin II-mediated effects.[3]
We determined the relationship between atrial natriuretic peptide (ANP) and blood pressure in anesthetized, normotensive rats. We studied the relationship between NEP inhibition and elevation of plasma cGMP evoked by ANP in the absence and presence of AHU-377, an ester prodrug of LBQ657 and a component of LCZ696 [1, 2]. Finally, using telemetry, we assessed the antihypertensive effects of AHU-377 in conscious Dahl-SS and DOCA-salt models of hypertension [4]. |
| References |
[1]. Ksander GM, et al. Dicarboxylic acid dipeptide neutral endopeptidase inhibitors. J Med Chem. 1995 May 12;38(10):1689-700.
[2]. Voors AA, et al. The potential role of valsartan + AHU377 ( LCZ696 ) in the treatment of heart failure. Expert Opin Investig Drugs. 2013 Aug;22(8):1041-7. [3]. von Lueder TG, et al. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy. Circ Heart Fail. 2015 Jan;8(1):71-8. [4]. Hegde, L.G., et al. Comparative efficacy of AHU-377, a potent neprilysin inhibitor, in two rat models of volume-dependent hypertension. BMC Pharmacol 11, P33 (2011). |
| Molecular Formula |
C24H29CANO5
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|---|---|
| Molecular Weight |
451.5688
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| Exact Mass |
860.356086
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| Elemental Analysis |
C, 66.96; H, 6.56; Ca, 4.65; N, 3.25; O, 18.58
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| CAS # |
1369773-39-6
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| Related CAS # |
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 |
92045585
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| Appearance |
White to off-white solid
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| LogP |
5.782
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
22
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| Heavy Atom Count |
61
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| Complexity |
544
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| Defined Atom Stereocenter Count |
4
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| SMILES |
[Ca+2].O(C([H])([H])C([H])([H])[H])C([C@]([H])(C([H])([H])[H])C([H])([H])[C@@]([H])(C([H])([H])C1C([H])=C([H])C(C2C([H])=C([H])C([H])=C([H])C=2[H])=C([H])C=1[H])N([H])C(C([H])([H])C([H])([H])C(=O)O[H])=O)=O
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| InChi Key |
DDLCKLBRBPYKQS-OXXXZDCLSA-L
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| InChi Code |
InChI=1S/2C24H29NO5.Ca/c2*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;/h2*4-12,17,21H,3,13-16H2,1-2H3,(H,25,26)(H,27,28);/q;;+2/p-2/t2*17-,21+;/m11./s1
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| Chemical Name |
calcium;4-[[(2S,4R)-5-ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl]amino]-4-oxobutanoate
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| Synonyms |
AHU337; LCZ696; AHU-337; LCZ 696; AHU 337; 1369773-39-6; AHU-377 hemicalcium salt; Sacubitril calcium; Sacubitril hemicalcium salt; AHU-377 calcium salt; 8F45HCQ47Q; UNII-8F45HCQ47Q; 4-(((2S,4R)-5-Ethoxy-4-methyl-5-oxo-1-(4-phenylphenyl)pentan-2-yl)amino)-4-oxobutanoic acid calcium salt; LCZ696
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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) |
DMSO : ~125 mg/mL (~290.35 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 6.25 mg/mL (14.52 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 62.5 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: ≥ 6.25 mg/mL (14.52 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 62.5 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: ≥ 6.25 mg/mL (14.52 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 | 2.2145 mL | 11.0725 mL | 22.1450 mL | |
| 5 mM | 0.4429 mL | 2.2145 mL | 4.4290 mL | |
| 10 mM | 0.2214 mL | 1.1072 mL | 2.2145 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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