RT Journal Article
SR Electronic
T1 Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 736
OP 745
DO 10.1124/jpet.108.142976
VO 327
IS 3
A1 Marc Iglarz
A1 Christoph Binkert
A1 Keith Morrison
A1 Walter Fischli
A1 John Gatfield
A1 Alexander Treiber
A1 Thomas Weller
A1 Martin H. Bolli
A1 Christoph Boss
A1 Stephan Buchmann
A1 Bruno Capeleto
A1 Patrick Hess
A1 Changbin Qiu
A1 Martine Clozel
YR 2008
UL http://jpet.aspetjournals.org/content/327/3/736.abstract
AB 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 ETA/ETB 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 ETA and ETB 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 (ETA receptors) and sarafotoxin S6c-induced contractions in isolated rat trachea (ETB 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. The American Society for Pharmacology and Experimental Therapeutics