MK-571 sodium salt hydrate
(Synonyms: L-660711) 目录号 : GC14980
A selective CysLT1 receptor antagonist
Cas No.:115103-85-0
Sample solution is provided at 25 µL, 10mM.
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- Purity: >98.00%
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- Datasheet
| Cell experiment [1]: | |
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Cell lines |
MDCKII-MRP2 |
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Preparation Method |
Prior to the addition of calcein-AM, cells were pre-exposed to increasing concentrations of the MRP-inhibitors (20-100 µM), MK-571, montelukast, zafirlukast or probenecid, for 15 minutes. Cells were then incubated with calcein-AM (0.25µM) in the dark for 30 minutes at 37°C and 5% CO2. Cells were then washed 3 times in ice-cold PBS and calcein-retentions were determined by using an FLx 800 fluorimeter. |
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Reaction Conditions |
20-100 µM; 15 min |
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Applications |
In the MDCKII-MRP2 cells, pre-exposure to MK-571 showed a 3-fold increase in calcein retention, whereas montelukast coexposure showed almost a 5-fold increase. |
| Animal experiment [2]: | |
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Animal models |
Sprague-Dawley male rats |
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Preparation Method |
Sprague-Dawley male rats were divided into 3 study groups: a sham-operated group, a kidney I/R group, and a group treated with MK-571 before the kidney I/R injury: MK-571 (5 mg/kg) was administered intraperitoneally 15 minutes before ischemia and every 12 hours after reperfusion up to 24 hours. |
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Dosage form |
5 mg/kg; i.p. |
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Applications |
In MK-571-treated rats, Penh was muted during methacholine challenge test. Treatment with MK-571, a leukotriene D4 inhibitor, effectively attenuates airway hypersensitivity, pulmonary inflammatory response, and lung and kidney injury. |
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References: [1] Roy U, et al. Montelukast is a potent and durable inhibitor of multidrug resistance protein 2-mediated efflux of taxol and saquinavir. Biol Pharm Bull. 2009 Dec;32(12):2002-9. | |
MK-571 sodium salt hydrate, as a potent and specific antagonist of leukotriene D4 action, used for treatment of asthma[1].
In vitro test it shown that with 0.01-100 μM MK-571 reduced the export of 3H-S1P from erythrocytes in a concentration-dependent manner[2]. In vitro efficacy test it exhibited that 12.5-50 μM MK-571 in both aortic and brain derived ECs has more obvious supress-the efflux of agents rate than that of verapamil[3]. MK-571 has inhibition against LTC4 transport with IC50 of 1.0 μM[4].
In vivo, treatment with 8-32 mg/kg MK-571 intravenously in mice caused dose-dependent protection against acetic-acid-induced abdominal constriction with ED50 of 30 mg/kg[5]. In vivo, mice were instilled after endotoxin instillation at doses of 15, 35, or 50 mg/kg, MK-571 obviously inhibited the influx of inflammatory cells and reduced pro-inflammatory cytokines in BALF in a dose-dependent manner[6]. In addition, 10 ug/eye completely inhibited in vivo chemotactic responses to LTD4, and partially inhibited (54%) the responses to ovalbumin[7]. In vivo, pretreatment with 1 mg/kg MK-571 orally markedly inhibited the OA(ovalbumin)-induced EO (eosinophils) migration[8] . Treatment with 1 mg/kg/day MK-571 for at least 1 day after injury in a model of balloon catheter injury of rat carotid artery, MK-571 had effective inhibition of myointimal VSMC (vascular smooth muscle cell) proliferation, with a 58% reduction of 5-bromo-2'-deoxyuridine (BrdU) uptake in the neointima and 69% reduction of neointimal thickening[9].
References:
[1] Tocco DJ, et al. Interspecies differences in stereoselective protein binding and clearance of MK-571. Drug Metab Dispos. 1990 Jul-Aug;18(4):388-92.
[2] Christensen PM, et al. Apolipoprotein M mediates sphingosine-1-phosphate efflux from erythrocytes. Sci Rep. 2017 Nov 8;7(1):14983.
[3] Eilers M, et al. MRP (ABCC) transporters-mediated efflux of anti-HIV drugs, saquinavir and zidovudine, from human endothelial cells. Exp Biol Med (Maywood). 2008 Sep;233(9):1149-60.
[4] Schaub T, et al. ATP-dependent leukotriene export from mastocytoma cells. FEBS Lett. 1991 Feb 11;279(1):83-6.
[5] G?k S, et al. The antinociceptive effect of leukotriene D(4) receptor antagonist, MK-571, in mice: possible involvement of opioidergic mechanism. Eur J Pharmacol. 1999 Dec 15;386(2-3):195-200.
[6] Hao Q, et al. Mesenchymal Stem Cell-Derived Extracellular Vesicles Decrease Lung Injury in Mice. J Immunol. 2019 Oct 1;203(7):1961-1972.
[7] Chan CC, et al. Eosinophil-eicosanoid interactions: inhibition of eosinophil chemotaxis in vivo by a LTD4-receptor antagonist. Eur J Pharmacol. 1990 Dec 4;191(3):273-80.
[8] Foster A, et al. Peptide leukotriene involvement in pulmonary eosinophil migration upon antigen challenge in the actively sensitized guinea pig. Int Arch Allergy Appl Immunol. 1991;96(3):279-84.
[9] Porreca E, et al. Cysteinyl leukotriene D4 induced vascular smooth muscle cell proliferation: a possible role in myointimal hyperplasia. Thromb Haemost. 1996 Jul;76(1):99-104.
MK-571 钠盐水合物，作为白三烯 D4 作用的强效特异性拮抗剂，用于治疗哮喘[1]。
体外试验表明，0.01-100 μM MK-571 以浓度依赖性方式减少红细胞中 3H-S1P 的输出[2]。体外药效试验表明，12.5-50 μM MK-571在主动脉和脑源性ECs中均比维拉帕米[3]具有更明显的抑制药物流出率的作用。 MK-571 抑制 LTC4 转运，IC50 为 1.0 μM[4]。
在体内，小鼠静脉注射 8-32 mg/kg MK-571 后，ED50 为 30 mg/kg[5]，对醋酸诱导的腹部收缩产生剂量依赖性保护作用.在体内，小鼠以15、35或50 mg/kg的剂量滴注内毒素后，MK-571以剂量依赖的方式明显抑制BALF中炎症细胞的流入和促炎细胞因子的减少[ 6]。此外，10 ug/eye 完全抑制体内对 LTD4 的趋化反应，并部分抑制 (54%) 对卵清蛋白的反应[7]。在体内，口服 1 mg/kg MK-571 预处理可显着抑制 OA（卵清蛋白）诱导的 EO（嗜酸性粒细胞）迁移[8]。在大鼠颈动脉球囊导管损伤模型中，用 1 mg/kg/day MK-571 治疗至少 1 天后，MK-571 可有效抑制肌内膜 VSMC（血管平滑肌细胞）增殖，具有 58新内膜中 5-溴-2'-脱氧尿苷 (BrdU) 摄取减少 %，新内膜增厚减少 69%[9]。
| Cas No. | 115103-85-0 | SDF | |
| 别名 | L-660711 | ||
| 化学名 | 5-(3-(2-(7-Chloroquinolin-2-yl)ethenyl)phenyl)-8-dimethylcarbamyl-4,6-dithiaoctanoic acid sodium salt hydrate | ||
| Canonical SMILES | O=C([O-])CCSC(C1=CC=CC(/C=C/C2=NC3=CC(Cl)=CC=C3C=C2)=C1)SCCC(N(C)C)=O.[Na+] | ||
| 分子式 | C26H26ClN2NaO3S2·xH2O | 分子量 | 537.07 (anhydrous basis) |
| 溶解度 | ≥ 33 mg/mL in DMSO | 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 | 1.862 mL | 9.3098 mL | 18.6195 mL |
| 5 mM | 0.3724 mL | 1.862 mL | 3.7239 mL |
| 10 mM | 0.1862 mL | 0.931 mL | 1.862 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 | ||||||||||
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，
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。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
MK-571, a Cysteinyl Leukotriene Receptor 1 Antagonist, Inhibits Hepatitis C Virus ReplicationAntimicrob Agents Chemother.2020 May 21;64(6):e02078-19PMID: 32179525DOI: 10.1128/AAC.02078-19
The quinoline MK-571 is the most commonly used inhibitor of multidrug resistance protein-1 (MRP-1) but was originally developed as a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist. While studying the modulatory effect of MRP-1 on anti-hepatitis C virus (HCV) direct-acting antiviral (DAA) efficiency, we observed an unexpected anti-HCV effect of compound MK-571 alone. This anti-HCV activity was characterized in Huh7.5 cells stably harboring a subgenomic genotype 1b replicon. A dose-dependent decrease of HCV RNA levels was observed upon MK-571 administration, with a 50% effective concentration (EC50 ± standard deviation) of 9 ± 0.3 μM and a maximum HCV RNA level reduction of approximatively 1 log10 MK-571 also reduced the replication of the HCV full-length J6/JFH1 model in a dose-dependent manner. However, probenecid and apigenin homodimer (APN), two specific inhibitors of MRP-1, had no effect on HCV replication. In contrast, the CysLTR1 antagonist SR2640 increased HCV-subgenomic replicon (SGR) RNA levels in a dose-dependent manner, with a maximum increase of 10-fold. In addition, a combination of natural CysLTR1 agonist (LTD4) or antagonists (zafirlukast, cinalukast, and SR2640) with MK-571 completely reversed its antiviral effect, suggesting its anti-HCV activity is related to CysLTR1 rather to MRP-1 inhibition. In conclusion, we showed that MK-571 inhibits HCV replication in hepatoma cell cultures by acting as a CysLTR1 receptor antagonist, thus unraveling a new host-virus interaction in the HCV life cycle.
Development of novel leukotriene--based anti-asthma drugs: MK-886 and MK-571
Agents Actions Suppl1991;34:179-87.PMID: 1793062
A potent, selective and orally active receptor antagonist of leukotriene D4, MK-571, was discovered and developed from a styrylquinoline lead structure based on a hypothetical model of the leukotriene D4 receptor. MK-571 blocks the action of LTD4 in animals and man, and is effective in a number of animal models of antigen-induced bronchoconstriction at plasma concentration at or below 2 micrograms/mL. MK-571 also blocks antigen-induced asthmatic responses in man. In addition a series of 2-indolealkanoic acids was discovered to be inhibitors of leukotriene biosynthesis. From this series, MK-886, a nanomolar inhibitor of leukotriene biosynthesis was developed. The mechanism of action of MK-886 has been found to be the inhibition of activation of the 5-lipoxygenase enzyme. This inhibition is mediated by interaction with a specific 18 kD protein termed 5-lipoxygenase activating protein (FLAP). MK-886 is an inhibitor of leukotriene biosynthesis and of antigen-induced bronchoconstriction in animal models and in asthmatic men.
MK-571 attenuates kidney ischemia and reperfusion-induced airway hypersensitivity in rats
Transplant Proc.2014 May;46(4):1127-30.PMID: 24815144DOI: 10.1016/j.transproceed.2013.12.041
Objective: Reperfusion of the rat kidney has been shown to up-regulate cysteinyl leukotriene-1 receptor, an asthma-associated gene in human bronchioles, and increase expression of leukotriene D4. In this study, we aimed to investigate the efficacy of MK-571, a leukotriene D4 inhibitor, against hypersensitivity induced by kidney ischemia and reperfusion (I/R)-associated acute kidney injury. Methods: Sprague-Dawley male rats were divided into 3 study groups: a sham-operated group, a kidney I/R group, and a group treated with MK-571 before the kidney I/R injury: MK-571 (5 mg/kg) was administered intraperitoneally 15 minutes before ischemia and every 12 hours after reperfusion up to 24 hours. Ischemia was conducted by bilateral occlusion of renal pedicles for 45 minutes, followed by releasing the clamps and closing the abdominal incision. Respiratory function was tested 24 hours after reperfusion, with the use of a 2-chamber whole body plethysmograph for conscious rats. Blood samples, pulmonary bronchoalveolar lavage fluid, and lung tissues were collected at the end of study. In 10 rats, urine was collected at baseline and the end of study. Results: Compared with the sham group, kidney I/R injury markedly increased enhanced pause (Penh) index during methacholine challenge test (P < .05), suggesting airway hypersensitivity; it also increased in inflammatory response and levels of hydroxyl radical production and lipid peroxidation in the lungs. In contrast, in MK-571-treated rats, Penh was muted during methacholine challenge test (P < .05). Conclusions: Kidney I/R injury induces airway hypersensitivity to methacholine challenge test and inflammatory response and oxidative stress in the lungs. Treatment with MK-571, a leukotriene D4 inhibitor, effectively attenuates airway hypersensitivity, pulmonary inflammatory response, and lung and kidney injury.
Clinical experience with MK-571. A potent and specific LTD4 receptor antagonist
Ann N Y Acad Sci.1991;629:148-56. PMID: 1659276 DOI: 10.1111/j.1749-6632.1991.tb37972.x
Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. Amirav I, Pawlowski N. N Engl J Med. 1991 May 2;324(18):1288. doi: 10.1056/NEJM199105023241815. PMID: 1849613 No abstract available. Inhibition of exercise-induced bronchoconstriction by MK-571, a potent leukotriene D4-receptor antagonist. Manning PJ, Watson RM, Margolskee DJ, Williams VC, Schwartz JI, O'Byrne PM. N Engl J Med. 1990 Dec 20;323(25):1736-9. doi: 10.1056/NEJM199012203232504. PMID: 2174121 Clinical Trial. Regulation of the production and action of leukotrienes by MK-571 and MK-886. Ford-Hutchinson AW. Adv Prostaglandin Thromboxane Leukot Res. 1991;21A:9-16. PMID: 1847788 Clinical Trial. No abstract available. Development of novel leukotriene--based anti-asthma drugs: MK-886 and MK-571. Young RN. Agents Actions Suppl. 1991;34:179-87. PMID: 1793062 Review. The preclinical and clinical pharmacology of SK&F 104353, a potent and selective peptidoleukotriene receptor antagonist. Torphy TJ, Faiferman I, Gleason JG, Hall RF, Lewis MA, Broom C, Helfrich HM, Newton JF, Hay DW.
MK-571, a potent antagonist of leukotriene D4-induced bronchoconstriction in the human
Am Rev Respir Dis.1991 Sep;144(3 Pt 1):617-21.PMID: 1892302DOI: 10.1164/ajrccm/144.3_Pt_1.617
MK-571 is a novel leukotriene D4/E4 (LTD4/E4) receptor antagonist. The ability of MK-571 to inhibit LTD4-induced bronchoconstriction was examined both in six healthy volunteers and in six asthmatic subjects in a double-blind, placebo-controlled, randomized crossover study design. LTD4 challenges were performed during a constant infusion with placebo or the active compound. The provocative concentration of LTD4 causing a 35% decrease in SGaw (PC35 SGaw) was 4.8 +/- 0.6 x 10(-5) M (mean +/- SEM) in healthy volunteers and 1.8 +/- 0.7 x 10(-6) M in asthmatic subjects during placebo treatment. Intravenous MK-571 (1,500, 86, or 28 mg) inhibited the LTD4-induced bronchoconstriction completely in healthy volunteers, up to an inhaled concentration of 10(-4) M LTD4. In asthmatic subjects, 28 mg MK-571 caused a significant, at least 44-fold, rightward shift of the dose-response curve to LTD4, whereas 277 mg shifted the dose-response curve at least 84-fold to the right. MK-571 is therefore a potent antagonist of LTD4-induced bronchoconstriction in both normal volunteers and asthmatic patients. MK-571 also caused a small but significant increase in baseline airway caliber in asthmatic patients, suggesting the presence of LTD4 in asthmatic airways and thus providing further support to a role for sulfidopeptide leukotrienes in the pathogenesis of asthma.