Background:

ACT-132577 is a dual antagonist of ETA and ETB receptors with IC50 values of 3.4nM and 987nM, respectively [1].

ACT-132577 is a major metabolite of macitentan which is a dual ET receptor antagonist with strong affinity for the tissues. Macitentan is metabolized into ACT-132577 in vivo. ACT-132577 is also a dual ET receptor antagonist and has a longer half-life than its parent compound. In assays using microsomal membranes of CHO cells overexpressing human ETA and ETB receptors, ACT-132577 shows potent effects on ETA and ETB receptors with IC50 values of 3.4nM and 987nM, respectively. In the in vitro functional assay, ACT-132577 completely inhibits the intracellular calcium increase induced by ET-1with IC50 values of 14nM, 5.8nM and 10.9nM in HPASMC, RASMC and m3T3 cells, respectively. ACT-132577 also causes a significant reduction of sarafotoxin S6c-induced contraction in isolated rat trachea [1].

In normotensive rats, administration of macitentan increases plasma ET-1 concentration. In hypertensive DOCA-salt rats, macitentan decreases mean arterial blood pressure. Besides that, macitentan suppresses the development of pulmonary hypertension and right ventricle hypertrophy in the monocrotaline model of pulmonary hypertension as well as in the streptozotocin model of diabetes [1].

参考文献:
[1] Iglarz M, Binkert C, Morrison K, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. Journal of Pharmacology and Experimental Therapeutics, 2008, 327(3): 736-745.