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.