Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist

J Pharmacol Exp Ther. 2008 Dec;327(3):736-45. doi: 10.1124/jpet.108.142976. Epub 2008 Sep 9.


Macitentan, also called Actelion-1 or ACT-064992 [N-[5-(4-bromophenyl)-6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-N'-propylaminosulfonamide], is a new dual ET(A)/ET(B) endothelin (ET) receptor antagonist designed for tissue targeting. Selection of macitentan was based on inhibitory potency on both ET receptors and optimization of physicochemical properties to achieve high affinity for lipophilic milieu. In vivo, macitentan is metabolized into a major and pharmacologically active metabolite, ACT-132577. Macitentan and its metabolite antagonized the specific binding of ET-1 on membranes of cells overexpressing ET(A) and ET(B) receptors and blunted ET-1-induced calcium mobilization in various natural cell lines, with inhibitory constants within the nanomolar range. In functional assays, macitentan and ACT-132577 inhibited ET-1-induced contractions in isolated endothelium-denuded rat aorta (ET(A) receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ET(B) receptors). In rats with pulmonary hypertension, macitentan prevented both the increase of pulmonary pressure and the right ventricle hypertrophy, and it markedly improved survival. In diabetic rats, chronic administration of macitentan decreased blood pressure and proteinuria and prevented end-organ damage (renal vascular hypertrophy and structural injury). In conclusion, macitentan, by its tissue-targeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats. This profile makes macitentan a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / drug effects
  • Calcium Signaling / drug effects
  • Cell Line
  • Drug Delivery Systems
  • Endothelin A Receptor Antagonists
  • Endothelin B Receptor Antagonists
  • Endothelin Receptor Antagonists*
  • Hypertension, Pulmonary / drug therapy
  • Hypertrophy, Right Ventricular / drug therapy
  • Kidney Diseases / prevention & control
  • Pyrimidines / administration & dosage
  • Pyrimidines / metabolism
  • Pyrimidines / pharmacology*
  • Rats
  • Sulfonamides / administration & dosage
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*
  • Survival Rate
  • Trachea / drug effects
  • Vasoconstriction / drug effects


  • Endothelin A Receptor Antagonists
  • Endothelin B Receptor Antagonists
  • Endothelin Receptor Antagonists
  • Pyrimidines
  • Sulfonamides
  • macitentan