MLN-4760
(Synonyms: GL-1001) 目录号 : GC31354
MLN-4760是一种选择性的人血管紧张素转换酶2（ACE2；IC50=0.44nM）抑制剂，MLN-4760可高亲和力地结合ACE2的活性位点锌离子，模拟肽水解过程中的过渡态，从而阻断血管紧张素II向血管紧张素(1-7)的转化。
Cas No.:305335-31-3
Sample solution is provided at 25 µL, 10mM.
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MLN-4760 is a selective inhibitor of human angiotensin-converting enzyme 2 (ACE2; IC₅₀=0.44nM). MLN-4760 binds with high affinity to the zinc ion in the active site of ACE2, mimicking the transition state during peptide hydrolysis, thereby blocking the conversion of angiotensin II to angiotensin(1-7)[1-2]. MLN-4760 is primarily used in studies related to kidney diseases, cardiovascular diseases, and inflammatory bowel disease[3-4].
In vitro, treatment of high glucose (HG)-cultured human umbilical vein endothelial cells (HUVECs) with MLN-4760 (100nM) for 24 hours, MLN-4760 significantly inhibited the expression of ACE2 and Ang-(1-7) in HUVECs. MLN-4760 also downregulated the activity of the insulin signaling pathway (IRS-1/PI3K/Akt/eNOS) and exacerbated oxidative stress and inflammatory responses[5]. Pretreatment of high glucose (30mM)-cultured human renal tubular epithelial cells (HK2) with MLN-4760 (5μM) for 24 hours, followed by intervention with Dapagliflozin (10μM) for 24 hours, MLN-4760 significantly reversed the Dapagliflozin-induced upregulation of ACE2 expression and inhibition of epithelial-mesenchymal transition (EMT), while restoring the expression level of the pro-fibrotic factor TGF-β1[6].
In vivo, administration of MLN-4760 (1mg/kg/day) via subcutaneous implantation of a mini-osmotic pump for 14 days in spontaneously hypertensive rats, MLN-4760 significantly increased the body weight gain rate and the visceral fat-to-body weight ratio, while elevating the concentration of hydrogen sulfide (H₂S) in both plasma and cardiac tissues[7]. MLN-4760 (1mg/kg/day) administered via subcutaneous implantation of a mini-osmotic pump for 14 days in spontaneously hypertensive rats, MLN-4760 significantly reduced the osmotic resistance of red blood cells and induced morphological abnormalities in erythrocytes[8].
References:
[1] Kluknavsky M, Micurova A, Cebova M, et al. MLN-4760 Induces Oxidative Stress without Blood Pressure and Behavioural Alterations in SHRs: Roles of Nfe2l2 Gene, Nitric Oxide and Hydrogen Sulfide. Antioxidants (Basel). 2022 Dec 1;11(12):2385.
[2] Joshi S, Balasubramanian N, Vasam G, et al. Angiotensin converting enzyme versus angiotensin converting enzyme-2 selectivity of MLN-4760 and DX600 in human and murine bone marrow-derived cells. Eur J Pharmacol. 2016 Mar 5;774:25-33.
[3] Jasenovec T, Radosinska D, Kollarova M, et al. Effects of Taxifolin in Spontaneously Hypertensive Rats with a Focus on Erythrocyte Quality. Life (Basel). 2022 Dec 7;12(12):2045.
[4] Berenyiova A, Bernatova I, Zemancikova A, et al. Vascular Effects of Low-Dose ACE2 Inhibitor MLN-4760-Benefit or Detriment in Essential Hypertension? Biomedicines. 2021 Dec 24;10(1):38.
[5] Wang Y, Fu W, Xue Y, et al. Ginsenoside Rc Ameliorates Endothelial Insulin Resistance via Upregulation of Angiotensin-Converting Enzyme 2. Front Pharmacol. 2021 Feb 23;12:620524.
[6] Wang S, Zhang X, Chong N, et al. Dapagliflozin ameliorates high glucose-induced epithelial-mesenchymal transition via up-regulating ACE2 mediated by EZH2 in diabetic nephropathy. J Endocrinol Invest. 2025 Oct;48(10):2499-2509.
[7] Cacanyiova S, Cebova M, Simko F, et al. The effect of zofenopril on the cardiovascular system of spontaneously hypertensive rats treated with the ACE2 inhibitor MLN-4760. Biol Res. 2023 Oct 25;56(1):55.
[8] Jasenovec T, Radosinska D, Kollarova M, et al. Angiotensin System Modulations in Spontaneously Hypertensive Rats and Consequences on Erythrocyte Properties; Action of MLN-4760 and Zofenopril. Biomedicines. 2021 Dec 14;9(12):1902.
MLN-4760是一种选择性的人血管紧张素转换酶2（ACE2；IC50=0.44nM）抑制剂，MLN-4760可高亲和力地结合ACE2的活性位点锌离子，模拟肽水解过程中的过渡态，从而阻断血管紧张素II向血管紧张素(1-7)的转化[1-2]。MLN-4760主要被用于肾脏疾病、心血管疾病以及炎症性肠病的相关研究中[3-4]。
在体外，MLN-4760（100nM）处理高葡萄糖（HG）培养的人脐静脉内皮细胞（HUVECs）24小时，随后以胰岛素（100nM）刺激30分钟，MLN-4760显著抑制HUVECs细胞中ACE2和Ang-(1-7)的表达，同时下调胰岛素信号通路（IRS-1/PI3K/Akt/eNOS）的活性，并加剧氧化应激和炎症反应[5]。MLN-4760（5μM）预处理高葡萄糖（30mM）培养的人肾小管上皮细胞（HK2）24小时，随后以Dapagliflozin（10μM）干预24小时，MLN-4760显著逆转Dapagliflozin诱导的ACE2表达上调和上皮-间质转化（EMT）抑制，同时恢复促纤维化因子TGF-β1的表达水平[6]。
在体内，MLN-4760（1mg/kg/day）通过皮下植入微型渗透泵连续给药自发性高血压大鼠14天，MLN-4760显著增加大鼠的体重增长率和内脏脂肪/体重比值，同时升高血浆及心脏组织中硫化氢（H₂S）浓度 [7]。MLN-4760（1mg/kg/day）通过皮下植入微型渗透泵连续给药自发性高血压大鼠14天，MLN-4760显著降低大鼠红细胞的渗透抵抗性，并诱导红细胞形态异常[8]。
| Cell experiment [1]: | |
Cell lines | Human Umbilical Vein Endothelial Cells (HUVECs) |
Preparation Method | HUVECs were cultured in Ham's F-12K complete medium at 37°C in a humidified atmosphere of 5% CO₂. HUVECs were treated with the selective ACE2 inhibitor MLN-4760 at a concentration of 100nM for 24 hours. |
Reaction Conditions | 100nM; 24h |
Applications | MLN-4760 significantly downregulation of ACE2 and Mas protein expression in high glucose (HG)-treated HUVECs. MLN-4760 also upregulation of proinflammatory cytokines and oxidative stress. |
| Animal experiment [2]: | |
Animal models | Spontaneously Hypertensive Rats (SHR) |
Preparation Method | Rats were administered the specific ACE2 inhibitor MLN-4760 (1mg/kg/day) via subcutaneously implanted Alzet® mini-osmotic pumps (model 2002, pumping rate 0.5μL/hour) for 14 days. |
Dosage form | 1mg/kg/day; s.c.; Continuous infusion for 14 days. |
Applications | MLN-4760 administration led to a significant increase in body weight gain and visceral fat mass, elevated plasma Angiotensin II (Ang II) levels, and increased plasma hydrogen sulfide (H₂S) concentration. MLN-4760 also induced deterioration of erythrocyte morphology and osmotic resistance. |
References: | |
| Cas No. | 305335-31-3 | SDF | |
| 别名 | GL-1001 | ||
| Canonical SMILES | O=C(O)[C@H](CC1=CN=CN1CC2=CC(Cl)=CC(Cl)=C2)N[C@H](C(O)=O)CC(C)C | ||
| 分子式 | C19H23Cl2N3O4 | 分子量 | 428.31 |
| 溶解度 | DMSO: 200 mg/mL (466.95 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.3348 mL | 11.6738 mL | 23.3476 mL |
| 5 mM | 467 μL | 2.3348 mL | 4.6695 mL |
| 10 mM | 233.5 μL | 1.1674 mL | 2.3348 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
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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，
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 saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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