Macitentan

Macitentan is a dual antagonist of the endothelin (ET) receptors type A and B (IC₅₀s = 0.5 and 391 nM in a radioligand binding assay using recombinant ET_A and ET_B, respectively).¹ Macitentan inhibits intracellular Ca²⁺ increases induced by the endothelin isoform ET-1 in human pulmonary arterial smooth muscle cells (HPASMCs; IC₅₀ = 0.9 nM), contractions of isolated rat aortic rings (pA₂ = 7.6 for ET_A), and sarafotoxin S6c-induced contractions of isolated rat tracheal rings (pA₂ = 5.9 for ET_B). Macitentan increases plasma ET-1 concentrations in normotensive rats and decreases mean arterial blood pressure in DOCA-salt hypertensive rats (ED₅₀ = 1 mg/kg). Oral administration (30 mg/kg per day) prevents development of pulmonary hypertension and right ventricle hypertrophy in a rat model of hypertension induced by monocrotaline (Item No. 16666). It also decreases the number of vascular and tubule-interstitial lesions and amount of glomerular damage in a rat model of diabetes induced by streptozotocin (Item No. 13104). Formulations containing macitentan have been used for the treatment of pulmonary arterial hypertension.

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1. Iglarz, M., Binkert, C., Morrison, K., et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J. Pharmacol. Exp. Ther. 327(3), 736-745 (2008).