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.