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Ambrisentan

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	同义名 :	安贝生坦 ;LU 208075;BSF 208075;pulmonext.;Volibris;Ambrisentan. trade name Letairis
	CAS号 :	177036-94-1
	货号 :	A121424
	分子式 :	C₂₂H₂₂N₂O₄
	纯度 :	98%
	分子量 :	378.421
	MDL号 :	MFCD08672619
	存储条件：	粉末 Sealed in dry,2-8°C 液体 -20°C:3-6个月-80°C:12个月
	溶解度 :	DMSO: 105 mg/mL(277.47 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO 无水乙醇: 7 mg/mL(18.5 mM)，配合低频超声助溶，注意：无水乙醇开封后，易挥发，也会吸收空气中的水分，导致溶解能力下降，请避免使用开封较久的乙醇
	动物实验配方：

生物活性
靶点	ET-A
描述	Endothelin-1 (ET-1) is the most predominant isoform of an isopeptides family that has potent vasoconstrictor activity. ET-1 is mediated by two receptor subtypes, endothelin receptor type A (ET&lt;sub&gt;A&lt;/sub&gt;) and B (ET&lt;sub&gt;B&lt;/sub&gt;). Ambrisentan is a diphenyl propionic acid that acts as a potent ET&lt;sub&gt;A&lt;/sub&gt; antagonist. The affinity of ambrisentan for human ET&lt;sub&gt;A&lt;/sub&gt; expressed in CHO cells is 1 nM, and the K&lt;sub&gt;i&lt;/sub&gt; value of ambrisentan for ET&lt;sub&gt;A&lt;/sub&gt; in intact cells expressing human recombinant ET&lt;sub&gt;A&lt;/sub&gt; is 0.63 nM. In LS180 cells, the mRNA expressions of CYP3A4, CYP2C9, ABCB1, SLCO1B1, SLCO2B1, PXR were significantly induced by 50 µM ambrisentan after 4-day incubation. The same treatment also resulted in 5.1-fold induction of P-gp expression and 1.2-fold of PXR expression. Ambrisentan at the concentration from 0.1 - 20 µM had a dose-dependent effect on PXP activity in LS180 cells. In OATP1B1 over-expressing cell lines, ambrisentan inhibited intracellular 8-FcA fluorescence with an IC50 value at 27.3 ± 8.6 µM. Ambrisentan (0.1 – 100 nM) showed dose-dependent inhibition on specific [&lt;sup&gt;125&lt;/sup&gt;I]ET-1 binding in rat bladder. Nonlinear least-squares regression analysis showed two populations of [&lt;sup&gt;125&lt;/sup&gt;I]ET-1 binding sites for ambrisentan, one with high affinity (pIC50 = 9.4 ± 0.7 nM), and the other with low affinity (pIC50 = 7.7 ± 0.5 nM). Moreover, 6 nM ambrisentan increased the K&lt;sub&gt;d&lt;/sub&gt; value for specific [&lt;sup&gt;125&lt;/sup&gt;I]ET-1 binding in rat bladder 2.32 times compared to that in control group, whereas the effect on the B&lt;sub&gt;max&lt;/sub&gt; value was moderate.
作用机制	Ambrisentan is a propionic acid-based selective antagonist for ET&lt;sub&gt;A&lt;/sub&gt; that can be orally administrated to treat pulmonary arterial hypertension.

临床研究
NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT01467791	-		Unknown	January 2018	United States, Ohio ... 展开 >> University of Cincinnati Recruiting Cincinnati, Ohio, United States, 45267 Contact: Rebecca Ingledue 513-584-6252 ingledra@ucmail.uc.edu Principal Investigator: Robert P Baughman, MD Sub-Investigator: Peter Engel, MD 收起 <<
NCT01347216	-		Recruiting	June 2020	Belgium ... 展开 >> Dept. of Pneumology, University Recruiting Leuven, Belgium Contact: Marion Delcroix, MD, PhD Principal Investigator: Marion Delcroix, MD, PhD Germany DRK-Klinikum Köpenick Recruiting Berlin, Germany Contact: Christian Opitz, MD, PhD Principal Investigator: Christian Opitz, MD, PhD Lung Centre, University of Giessen Recruiting Giessen, Germany Contact: Ardeschir Ghofrani, MD, PhD Principal Investigator: Ardeschir Ghofrani, MD Sub-Investigator: Melanie Thamm, MD Department of Pulmology; Hannover Medical School Recruiting Hannover, Germany Contact: Marius M Hoeper Principal Investigator: Marius M Hoeper, MD, PhD Sub-Investigator: Karen Olsson, MD German Heart Centre Recruiting Munich, Germany Contact: Harald Kaemmerer, MD,. PhD Principal Investigator: Harald Kaemmerer, MD, PhD Ireland Mater Misericordiae Recruiting Dublin, Ireland Contact: Sean Gaine, MD, PhD Principal Investigator: Sean Gaine, MD, PhD Italy Department of Cardiovascular and Respiratory Sciences, University La Sapienza Recruiting Rome, Italy Contact: Dario Vizza, MD, PhD Principal Investigator: Dario Vizza, MD, PhD Switzerland Dept. for Rheumatology, University Hospital Recruiting Zurich, Switzerland Contact: Oliver Distler, MD, PhD Principal Investigator: Oliver Distler, MD, PhD 收起 <<
NCT02565030	-		Active, not recruiting	October 2021	United Kingdom ... 展开 >> Sheffield Teaching Hospitals NHS Foundation Trust Sheffield, South Yorkshire, United Kingdom, S10 2JF 收起 <<

实验方案

1mg

5mg

10mg

1 mM

5 mM

10 mM

2.64mL

0.53mL

0.26mL

13.21mL

2.64mL

1.32mL

26.43mL

5.29mL

2.64mL

参考文献

[1]Yokoyama Y, Osano A, et al. Endothelin-1 receptors in rat tissues: characterization by bosentan, ambrisentan and CI-1020. Biol Pharm Bull. 2014;37(3):461-5.

[2]Weiss J, Herzog M, Haefeli WE. Differential modulation of the expression of important drug metabolising enzymes and transporters by endothelin-1 receptor antagonists ambrisentan and bosentan in vitro. Eur J Pharmacol. 2011 Jun 25;660(2-3):298-304.

[3]Radiloff D, Zhao Y, et al. Anti-hypotensive treatment and endothelin blockade synergistically antagonize exercise fatigue in rats under simulated high altitude. PLoS One. 2014 Jun 24;9(6):e99309.

[4]Lee H, Yeom A, et al. Effect of Ambrisentan Therapy on the Expression of Endothelin Receptor, Endothelial Nitric Oxide Synthase and NADPH Oxidase 4 in Monocrotaline-induced Pulmonary Arterial Hypertension Rat Model. Korean Circ J. 2019 Sep;49(9):866-876.

[5]Muthuraman A, Nafisa K, et al. Role of ambrisentan (selective endothelin-A receptor antagonist) on cigarette smoke exposure induced cognitive impairment in Danio rerio. Life Sci. 2019 Apr 1;222:133-139.

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靶点

靶点	数值

ET-A