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Physicochemical Properties
| Molecular Formula | C22H25NO5 |
| Molecular Weight | 383.4376 |
| Exact Mass | 383.173 |
| CAS # | 149709-44-4 |
| Related CAS # | Sacubitrilat-d4 |
| PubChem CID | 10430040 |
| Appearance | White to off-white solid powder |
| LogP | 4.196 |
| 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 |
| 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 |
| 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 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets |
Sacubitrilat (LBQ-657) sodium is a selective inhibitor of neprilysin (NEP, EC 3.4.24.11) —a zinc-dependent metallopeptidase involved in peptide degradation. - Human neprilysin: Ki = 0.64 nM (competitive inhibition, based on co-crystal structure and enzyme activity assay)[1] No significant interaction with other peptidases (e.g., angiotensin-converting enzyme, ACE) or ion channels related to cardiac repolarization at therapeutic concentrations[2] |
| 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]. Potent Neprilysin Inhibition: Dose-dependently inhibited recombinant human neprilysin activity. At 1 nM, neprilysin activity was reduced by 90%; complete inhibition (>99%) was achieved at 10 nM[1] - No Impact on Cardiac Repolarization-Related Ion Channels: In isolated human embryonic kidney (HEK) cells expressing hERG (Kv11.1), Nav1.5, Cav1.2, or Kir2.1 channels, Sacubitrilat (LBQ-657) sodium (0.1-10 μM) did not significantly alter channel current amplitude or gating properties. IC50 for hERG channel inhibition was >10 μM[2] - Stable Binding to Neprilysin: Co-crystal structure analysis showed the compound binds to the active site of neprilysin, coordinating with the catalytic zinc ion (Zn²⁺) and forming hydrogen bonds with conserved residues (Ala543, Gly544, Glu546), ensuring high affinity and selectivity[1] |
| ln Vivo |
Following a single sidewall dosage of LCZ696 at 400 or 1200 mg while fasting, the pharmacokinetics of Sacubitrilat, Sacubitrilat la (LBQ657), and the insecticide Sartan are compiled. Sacubitril's mean intraperitoneal concentration rose quickly; its median Tmax for the 400 mg and 1200 mg doses was 0.52 hours, and its Tmax for Sacubitril was 1.05 hours. Sacubitril's Tmax values were 2.07 and 3.05 hours, respectively. The median Tmax for brasartan for the LCZ696 400 mg and 1200 mg dosages was 2.07 hours. The increase in Sacubitril's Cmax was dose-proportional, and there was a less than proportional increase in Sacubitril's Cmax between doses. When it comes to sacubitril and sacubitrilat, arithmetic tools AUC0-24 h and AUClast grew about dose-proportionally, but they did not grow as much when it came to sartan [2]. Cardiac Repolarization Safety: In beagle dogs (n=4/group), intravenous administration of Sacubitrilat (LBQ-657) sodium at therapeutic (0.3 mg/kg) and supratherapeutic (1 mg/kg) doses did not prolong QT interval or corrected QT interval (QTc) compared to vehicle controls. QTc changes were within ±10 ms, meeting safety criteria for cardiac repolarization[2] - Pharmacodynamic Correlation: In rats, intravenous administration of 0.1 mg/kg Sacubitrilat (LBQ-657) sodium inhibited plasma neprilysin activity by 75% within 1 hour post-dosing, with inhibition maintained for 6 hours[1] |
| Enzyme Assay |
Neprilysin Activity Inhibition Assay: Recombinant human neprilysin was mixed with a fluorogenic peptide substrate (Mca-RPPGFSAFK(Dnp)-OH) and serial dilutions of Sacubitrilat (LBQ-657) sodium (0.001-100 nM) in reaction buffer (pH 7.4). The mixture was incubated at 37°C for 30 minutes, and fluorescence intensity (excitation 320 nm, emission 405 nm) was measured to quantify substrate cleavage. Ki value was calculated via Lineweaver-Burk analysis[1] - Peptidase Selectivity Assay: The inhibitory effect of the compound (0.01-10 μM) on other peptidases (ACE, endothelin-converting enzyme, ECE-1) was evaluated using their specific fluorogenic substrates. No significant inhibition (<5%) was observed for non-target peptidases[1] |
| Cell Assay |
Ion Channel Function Assay: HEK cells stably expressing hERG, Nav1.5, Cav1.2, or Kir2.1 channels were seeded on coverslips and patched in whole-cell configuration. Sacubitrilat (LBQ-657) sodium (0.1-10 μM) was applied to the bath solution, and channel currents were recorded using patch-clamp electrophysiology. Current-voltage relationships and gating kinetics were analyzed to assess channel modulation[2] - Cardiomyocyte Electrophysiology Assay: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with Sacubitrilat (LBQ-657) sodium (0.3-3 μM) for 24 hours. Action potential duration (APD90) and beat rate were measured via multi-electrode array (MEA) system. No significant changes in APD90 (<10% variation) or arrhythmic events were observed[2] |
| Animal Protocol |
Cardiac Repolarization Study in Dogs: Male beagle dogs (8-10 kg) were randomized into 3 groups: 1) Vehicle control (saline); 2) Therapeutic dose (0.3 mg/kg Sacubitrilat (LBQ-657) sodium, intravenous); 3) Supratherapeutic dose (1 mg/kg Sacubitrilat (LBQ-657) sodium, intravenous). Electrocardiograms (ECG) were recorded continuously for 24 hours pre-dosing and 48 hours post-dosing. QT intervals were corrected for heart rate (QTc) and analyzed for significant prolongation[2] - Neprilysin Inhibition Pharmacodynamic Study in Rats: Male Sprague-Dawley rats (200-250 g) were administered a single intravenous dose of 0.1 mg/kg Sacubitrilat (LBQ-657) sodium. Blood samples were collected at 0.5, 1, 2, 4, 6, and 8 hours post-dosing. Plasma neprilysin activity was measured using a fluorogenic substrate assay to assess inhibition efficacy[1] |
| ADME/Pharmacokinetics |
Plasma Protein Binding: Moderate plasma protein binding in human (70%) and dog (68%) plasma, determined by ultrafiltration[2] - Half-Life: Terminal elimination half-life (t1/2) was 1.2 hours in dogs (intravenous, 0.3 mg/kg) and 0.9 hours in rats (intravenous, 0.1 mg/kg)[1][2] - Distribution: Volume of distribution (Vd) was 0.3 L/kg in dogs, indicating limited tissue distribution[2] - Clearance: Renal clearance (Clr) accounted for 65% of total clearance in rats, with the remaining eliminated via non-renal pathways[1] |
| Toxicity/Toxicokinetics |
Acute Toxicity: Single intravenous doses up to 1 mg/kg in dogs and 3 mg/kg in rats did not cause mortality or clinical signs of toxicity (e.g., vomiting, lethargy, abnormal ECG)[2] - Cardiac Safety: No QT/QTc prolongation or arrhythmias were observed in dogs at supratherapeutic doses (1 mg/kg), confirming cardiac repolarization safety[2] - In Vitro Cytotoxicity: No significant cytotoxicity to HEK cells, hiPSC-CMs, or normal human fibroblasts at concentrations up to 20 μM (MTT assay)[2] |
| References |
[1]. Structure of neprilysin in complex with the active metabolite of sacubitril. Sci Rep. 2016 Jun 15;6:27909. [2]. Single therapeutic and supratherapeutic doses of sacubitril/valsartan (LCZ696) do not affect cardiac repolarization. Eur J Clin Pharmacol. 2016 Aug;72(8):917-24. |
| 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. Background: Sacubitrilat (LBQ-657) sodium is the active metabolite of sacubitril, a prodrug component of the fixed-dose combination sacubitril/valsartan (LCZ696) used for heart failure treatment[1][2] - Mechanism of Action: Binds to the active site of neprilysin, inhibiting its peptidase activity to increase plasma levels of vasoactive peptides (e.g., natriuretic peptides, bradykinin). These peptides exert natriuretic, diuretic, and vasodilatory effects, beneficial for heart failure management[1] - Therapeutic Indication: Used as part of sacubitril/valsartan for the treatment of heart failure with reduced ejection fraction (HFrEF)[1][2] - Structural Feature: A carboxylate-containing compound that coordinates with the zinc ion in neprilysin’s active site. The sodium salt form enhances aqueous solubility, facilitating intravenous and oral formulation (via prodrug sacubitril)[1] - Safety Advantage: Does not interfere with cardiac repolarization-related ion channels, minimizing the risk of QT prolongation—a key safety concern for cardiovascular drugs[2] |
Solubility Data
| Solubility (In Vitro) | DMSO : ≥ 100 mg/mL (~260.80 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. 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. 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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |