生物活性

• 描述G protein-coupled receptor (GPCR) agonists through their receptors can transactivate protein tyrosine kinase receptors such as epidermal growth factor receptor and serine/threonine kinase receptors most notably transforming growth factor (TGF)-β receptor (TβRI).Several GPCR agonists such as Ang II, thrombin, ET-1 can mediate the transactivation of a multitude of protein tyrosine kinase receptors^[5]. The three structurally closely related peptides, named endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3), are among the most potent vasoconstrictors known in humans. They convey their action through binding to two G-protein coupled receptors called ETA and ETB. Among the three isopeptides, ET-1 appears to be the key player in the cardiovascular system. ET-2 and ET-3 are specifically expressed in the gastrointestinal tract and the brain, respectively. Macitentan is a dual ETA/ETB receptors antagonist designed through a deliberate discovery process to maximize endothelin-axis blockade while improving adverse-effect profiles with IC₅₀ of 0.5 nM and 391 nM for ETA and ETB, respectively. Macitentan is a dual endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH). The physicochemical properties of macitentan favor penetration into lung tissue, where macitentan predominantly exerts its effects. Macitentan is highly bound to plasma proteins. In a vivo experiment, Macitentan treatment at 1 mg/kg/day for five consecutive days stably reduced mean arterial blood pressure by -20 mmHg over the whole treatment period and made it returned to baseline about 48h after the last dose was given in Dahl salt-sensitive rats^[4].
• 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
  NCT01347216	-	-	Recruiting	June 2020	Belgium ... more >> 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 Collapse <<
  NCT01266265	-	-	Completed	-	-
  NCT01266265	-	-	Completed	-	-

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• 参考文献

• [1] Sen S, Chen S, et al. Renal, retinal and cardiac changes in type 2 diabetes are attenuated by macitentan, a dual endothelin receptor antagonist. Life Sci. 2012 Oct 15;91(13-14):658-68.

  [2] Iglarz M, Binkert C, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008 Dec;327(3):736-45.

  [4] The Discovery of N‑[5-(4-Bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]‑N′‑propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist

  [5] Sharifat N, Mohammad Zadeh G, Ghaffari MA, Dayati P, Kamato D, Little PJ, Babaahmadi-Rezaei H. Endothelin-1 (ET-1) stimulates carboxy terminal Smad2 phosphorylation in vascular endothelial cells by a mechanism dependent on ET receptors and de novo protein synthesis. J Pharm Pharmacol. 2017 Jan;69(1):66-72. doi: 10.1111/jphp.12654. Epub 2016 Dec 1. PMID: 27905105.

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