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Macitentan

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Catalog No.
A1929
内皮素(ET)(A)和ET(B)受体拮抗剂
组合的产品项目
规格价格库存 数量
10mM (in 1mL DMSO)
¥ 1,940.00
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5mg
¥ 1,200.00
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25mg
¥ 3,800.00
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100mg
¥ 9,800.00
现货

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Background

Macitentan is a new dual ETA/ETB endothelin (ET) receptor antagonist, with mean IC50 values of 0.5 ± 0.2 nM (n= 17) to inhibit the binding of 125I-ET-1 to recombinant ETA receptors, and of 391±182 nM (n= 17) for ETB receptors in Chinese hamster ovary cells [1].

ETA and ETB are ET receptors, both of them mediate the detrimental actions of ET-1, and dual blockade of them may be necessary [1].

In microsomal membranes of human-ETA and ETB-overexpressing Chinese hamster ovary cells, macitentan inhibited the binding between 125I-ET-1 and recombinant ETA receptors, with a mean IC50 value of 0.5 ± 0.2 nM (n= 17). The mean IC50 value for ETB receptors was 391±182 nM (n= 17). Macitentan completely inhibited the effect that ET-1 increased intracellular calcium in non-recombinant cells [1].

Intravenous administrated macitentan had a volume of distribution largely exceeding plasma volume and a terminal half-life of 2 h in rats. Macitentan was hence metabolized to its major and the only circulating metabolite, a dual ET receptor antagonist, ACT-132577. ACT-132577 also had a volume of distribution greater than the plasma volume. It showed a longer half-life than macitentan in rats. In rat, multiple oral dosing of macitentan at a dose of 10 mg/kg led to 4 to 5-fold higher exposure levels of ACT-132577 than those of the parent compound [1].

Reference:
[1].  Marc Iglarz, Christoph Binkert, Keith Morrison, et al. Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist. Journal of Pharmacology and Experimental Therapeutics, 2008, 327:736-745.

Chemical Properties

Physical AppearanceA solid
StorageStore at -20°C
M.Wt588.27
Cas No.441798-33-0
FormulaC19H20Br2N6O4S
Solubility≥24.4mg/mL in DMSO
Chemical Name5-(4-bromophenyl)-6-[2-(5-bromopyrimidin-2-yl)oxyethoxy]-N-(propylsulfamoyl)pyrimidin-4-amine
SDFDownload SDF
Canonical SMILESCCCNS(=O)(=O)NC1=C(C(=NC=N1)OCCOC2=NC=C(C=N2)Br)C3=CC=C(C=C3)Br
运输条件试用装:蓝冰运输。 其他可选规格:常温运输或根据您的要求用蓝冰运输。
一般建议为了使其更好的溶解,请用37℃加热试管并在超声波水浴中震动片刻。不同厂家不同批次产品溶解度各有差异,仅做参考。若实验所需浓度过大至产品溶解极限,请添加助溶剂助溶或自行调整浓度。

试验操作

细胞实验 [1,2]:

细胞系

原发性人肺平滑肌细胞,微血管内皮细胞

溶解方法

该化合物在DMSO中的溶解度大于21.2 mg/mL。若获取更高浓度的溶液,可在37℃下孵育10分钟,随后在超声波浴中摇匀。-20℃以下可储存数月。

反应条件

IC50: 1 nM

应用

在原代人肺平滑肌细胞中,Macitentan完全抑制ET-1诱导的细胞内钙增加,IC50约为1 nM。Macitentan抑制分离的大鼠主动脉环中ET-1诱导的收缩和分离的大鼠气管环中S6c诱导的收缩,pA2分别为7.6和5.9。在微血管内皮细胞中,Macitentan预处理恢复管形成能力,减少间充质标记物的表达,恢复CD31的表达以及VEGF-A和VEGF-A165b之间的不平衡。

动物实验 [1,3-5]:

动物模型

高血压DOCA盐大鼠,肺动脉高压大鼠模型,SKOV3ip1卵巢癌模型

给药剂量

口服,25 mg/kg/day

应用

在血压正常的大鼠中,Macitentan增加血浆ET-1浓度。在高血压DOCA盐大鼠中,Macitentan以剂量依赖性方式降低平均动脉血压,10 mg/kg剂量降低了26 mm Hg,达到最大作用效果。在肺动脉高压大鼠模型中,口服Macitentan以剂量依赖性方式阻止肺动脉高压的发展和右心室肥大的发展,30 mg/kg/day达到最大功效。30 mg/kg/day慢性口服给药显著提高了肺动脉高压大鼠的42天生存期。口服Macitentan(25 mg/kg/day)阻止2型糖尿病中血管活性和纤维因子产生的增加、NF-κB活化、结构和功能变化以及细胞外基质蛋白产生增加。Macitentan(10 mg/kg,p.o.)与每周一次的5mg/kg紫杉醇组合显著降低了小鼠中HeyA8-MDR肿瘤的体重(体积)。Macitentan(10或50 mg/kg)和紫杉醇或macitentan(10 mg/kg)和顺铂组合治疗显著减少增殖的Ki-67阳性细胞的数量。Macitentan(100 mg/kg)和paclitaxel(5 mg/kg)联合治疗降低了肿瘤发生率,进一步降低了SKOV3ip1卵巢癌模型中肿瘤重量和腹水发生率。Macitentan与紫杉醇组合使用通过降低pVEGFR2、pAkt和pMAPK的水平来抑制ETR的磷酸化,并抑制肿瘤细胞的存活途径。Macitentan增强紫杉醇对肿瘤细胞分裂和凋亡的作用。

注意事项

由于实验环境的不同,实际溶解度可能与理论值略有不同,请测试室内所有化合物的溶解度。

References:

[1]. Marc Iglarz, Christoph Binkert, Keith Morrison, et al. Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist. Journal of Pharmacology and Experimental Therapeutics, 2008, 327:736-745.

[2]. Corallo C, et al. Bosentan and macitentan prevent the endothelial-to-mesenchymal transition (EndoMT) in systemic sclerosis: in vitro study. Arthritis Res Ther. 2016 Oct 6;18(1):228.

[3]. Sen S, et al. Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist. Life Sci. 2012 Apr 13.

[4]. Kim SJ, et al. Antivascular therapy for multidrug-resistant ovarian tumors by macitentan, a dual endothelin receptor antagonist. Transl Oncol. 2012 Feb;5(1):39-47.

[5].Kim S J, Kim J S, Kim S W, et al. Macitentan (ACT-064992), a tissue-targeting endothelin receptor antagonist, enhances therapeutic efficacy of paclitaxel by modulating survival pathways in orthotopic models of metastatic human ovarian cancer[J]. Neoplasia, 2011, 13(2): 167-IN12.

质量控制

化学结构

Macitentan