| 规格 | 价格 | 库存 | 数量 |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 250mg |
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| Other Sizes |
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| 靶点 |
NEP
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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| 体外研究 (In Vitro) |
Sacubitrilat (LBQ657) 具有独特的立体中心，是单一非对映异构体。 Sacubitrilat 通过复杂的反应网络（包括该化合物的所有官能团）与 NEP 活性位点结合后，表现出 5 nM 的高抑制功效 [1]。
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| 体内研究 (In Vivo) |
本研究总结了空腹期间单次侧剂量 400 或 1200 mg LCZ696 后 sacubitrilat、sacubitrilat la (LBQ657) 和杀虫剂沙坦的药代动力学。 400 mg 剂量的中位 Tmax 为 0.52 小时，1200 mg 剂量的中位 Tmax 为 1.05 小时，沙库巴曲的平均腹膜内浓度迅速上升。其次是沙库巴曲，相应的 Tmax 值分别为 2.07 小时和 3.05 小时。 LCZ696 400 mg 和 1200 mg 剂量的中位 Brasartan Tmax 为 2.07 小时。 Sacubitril 的 Cmax 显示出与剂量成比例的增加，而 Sacubitril 和 Sacubitril 的 Cmax 则显示出与剂量不成比例的增加。算术工具 AUC0-24 h 和 AUClast 显示沙坦的剂量比例增加较小，但 Sacubitril 和 Sacubitrilat 的剂量比例增加[2]。
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| 酶活实验 |
沙库比曲是活性奈普赖氨酸（NEP）抑制剂LBQ657的乙酯前药，也是LCZ696（沙库比曲利/缬沙坦）的一种成分。我们在此报道了LBQ657在2Å分辨率下与人类NEP复合物的三维结构。晶体结构揭示了占据活性位点的S1、S1’和S2’亚口袋的化合物的结合模式，与竞争抑制模式一致。抑制剂的P1’-联苯部分结合后诱导的拟合构象变化表明了其对结构同源的锌金属肽酶的选择性的解释[1]。
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| 动物实验 |
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] |
| 药代性质 (ADME/PK) |
This study provides pharmacokinetic (PK) parameters for LBQ657 following single oral doses of LCZ696 400 mg (therapeutic) and 1200 mg (supratherapeutic) in healthy male subjects under fasting conditions. [2]
After LCZ696 400 mg dose (N=81-82): Arithmetic mean AUC₀₋₂₄ was 122,000 h·ng/mL (SD 19,700, CV% 16.2); Arithmetic mean AUCₗₐₛₜ was 121,000 h·ng/mL (SD 22,200, CV% 18.3); Arithmetic mean Cₘₐₓ was 13,700 ng/mL (SD 2,490, CV% 18.2); Median Tₘₐₓ was 2.07 hours (range 1.05-5.07). [2] After LCZ696 1200 mg dose (N=82): Arithmetic mean AUC₀₋₂₄ was 364,000 h·ng/mL (SD 62,300, CV% 17.1); Arithmetic mean AUCₗₐₛₜ was 364,000 h·ng/mL (SD 62,400, CV% 17.1); Arithmetic mean Cₘₐₓ was 40,700 ng/mL (SD 6,990, CV% 17.2); Median Tₘₐₓ was 3.05 hours (range 2.05-5.07). [2] The Cₘₐₓ of LBQ657 showed a dose-proportional increase between the 400 mg and 1200 mg doses of LCZ696. The AUC increased approximately dose-proportionally. The half-life is mentioned to be short, but no specific t₁/₂ value is provided. The document also states that all LCZ696 analytes (including LBQ657) have high plasma protein binding, but no specific percentage is given. [2] |
| 毒性/毒理 (Toxicokinetics/TK) |
The safety assessment focused on the combination drug LCZ696. In this study of healthy subjects, single doses of LCZ696 400 mg and 1200 mg (which delivers LBQ657) were generally safe and well tolerated. The overall incidence of adverse events (AEs) was comparable to placebo (14.6% for each LCZ696 dose vs. 12.2% for placebo). Common AEs included headache, nasopharyngitis, postural dizziness, and nausea. Most AEs were mild and resolved without treatment. No deaths, serious AEs, or AEs leading to discontinuation were reported. No clinically significant changes in lab parameters, vital signs, or safety ECGs (beyond the primary QTc assessment) were observed. The study concluded that LCZ696 did not affect cardiac repolarization (QTc interval), indicating a low risk for drug-induced proarrhythmia related to its components, including LBQ657. [2]
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| 参考文献 | |
| 其他信息 |
A metabolite of LCZ696 with neprilysin inhibitory activity.
Sacubitrilat is a Neprilysin Inhibitor. The mechanism of action of sacubitrilat is as a Neprilysin Inhibitor. Sacubitrilat (LBQ657) is the active neprilysin (NEP) inhibitor metabolite generated from the prodrug sacubitril upon oral administration of LCZ696 (sacubitril/valsartan). LCZ696 is an angiotensin receptor neprilysin inhibitor (ARNI) approved to reduce the risk of cardiovascular death and hospitalization in chronic heart failure patients with reduced ejection fraction. This dedicated thorough QT (TQT) study demonstrated that single therapeutic (400 mg) and supratherapeutic (1200 mg) oral doses of LCZ696 did not prolong the QTc interval in healthy subjects, meeting the criteria set by ICH E14 guidelines. The mean baseline- and placebo-corrected QTcF (ΔΔQTcF) for both LCZ696 doses remained below 5 ms, with the upper bound of the 90% confidence interval below 10 ms at all time points. Assay sensitivity was confirmed using moxifloxacin (positive control). The study supports the cardiac repolarization safety profile of LCZ696 and, by extension, suggests no significant QT-prolonging risk from its components, including the NEP inhibitor LBQ657. [2] |
| 分子式 |
C22H25NO5
|
|---|---|
| 分子量 |
383.4376
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| 精确质量 |
383.173
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| 元素分析 |
C, 68.91; H, 6.57; N, 3.65; O, 20.86
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| CAS号 |
149709-44-4
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| 相关CAS号 |
Sacubitrilat-d4
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| PubChem CID |
10430040
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| 外观&性状 |
White to off-white solid powder
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| LogP |
4.196
|
| tPSA |
107.19
|
| 氢键供体(HBD)数目 |
3
|
| 氢键受体(HBA)数目 |
5
|
| 可旋转键数目(RBC) |
10
|
| 重原子数目 |
28
|
| 分子复杂度/Complexity |
521
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| 定义原子立体中心数目 |
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
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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
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| 化学名 |
(2R,4S)-4-(3-carboxypropanoylamino)-2-methyl-5-(4-phenylphenyl)pentanoic acid
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| 别名 |
Sacubitrilat; LBQ657; LBQ-657; LBQ 657
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| HS Tariff Code |
2934.99.9001
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| 存储方式 |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 运输条件 |
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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| 溶解度 (体外实验) |
DMSO: ~77 mg/mL (~200.8 mM)
Ethanol: ~77 mg/mL (~200.8 mM) |
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| 溶解度 (体内实验) |
配方 1 中的溶解度: ≥ 2.5 mg/mL (6.52 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。 *生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。 配方 2 中的溶解度: ≥ 2.5 mg/mL (6.52 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。 *20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。 View More
配方 3 中的溶解度: ≥ 2.5 mg/mL (6.52 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。 1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液)); 2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方): 10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline); 假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL； 3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例; 4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶; 5、为保证最佳实验结果，工作液请现配现用！ 6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们; 7、 以上所有助溶剂都可在 Invivochem.cn网站购买。 |
| 制备储备液 | 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 |
1、根据实验需要选择合适的溶剂配制储备液 (母液)：对于大多数产品，InvivoChem推荐用DMSO配置母液 (比如：5、10、20mM或者10、20、50 mg/mL浓度），个别水溶性高的产品可直接溶于水。产品在DMSO 、水或其他溶剂中的具体溶解度详见上”溶解度 (体外)”部分;
2、如果您找不到您想要的溶解度信息，或者很难将产品溶解在溶液中，请联系我们;
3、建议使用下列计算器进行相关计算（摩尔浓度计算器、稀释计算器、分子量计算器、重组计算器等）;
4、母液配好之后，将其分装到常规用量，并储存在-20°C或-80°C，尽量减少反复冻融循环。
计算结果:
工作液浓度： mg/mL；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL)。如该浓度超过该批次药物DMSO溶解度，请首先与我们联系。
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL ddH2O，混匀澄清。
(1) 请确保溶液澄清之后，再加入下一种溶剂 (助溶剂) 。可利用涡旋、超声或水浴加热等方法助溶；
(2) 一定要按顺序加入溶剂 (助溶剂) 。
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