Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist

Abstract

Macitentan, also called Actelion-1 or -6-(2-(5-bromopyrimidin-2-yloxy)ethoxy)-pyrimidin-4-yl]-NЈ-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 tissuetargeting 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.

A Pathogenetic Role for Endothelin-1 in Peritoneal Dialysis-Associated Fibrosis

“…39,50 In vitro, macitentan has been recently described to reduce the profibrotic response of dermal fibroblasts from systemic sclerosis patients. 51,52 It should be, however, noted that these drugs have shown significant side effects that have so far hampered their use as a general antifibrotic therapy. 29 This fact, together with the observation that PD fluid-associated complications develop in the long term, raises concerns about the widespread use of these drugs against functional deterioration of the peritoneal membrane.…”

“…47,52 Control and ET-1-overexpressing adenoviruses were from Vector Biolabs (Philadelphia, PA). The adenoviral vector expressing active TGF-b1 was provided by David Dichek (University of Washington, Seattle, WA) and has been previously described.…”

Treating pulmonary arterial hypertension: current treatments and future prospects

“…In hypertensive deoxycorticosterone acetate salt rats, macitentan reduced mean arterial blood pressure with an ED 50 value of 1 mg/kg, compared with 10 mg/kg for bosentan. With the maximal effective dose of macitentan (10 mg/kg), the decrease in blood pressure was maintained for ;40 h, whereas with bosentan (100 mg/kg) the response duration was 20 h [Iglarz et al 2008].…”

“…The monocrotaline rat model of pulmonary hypertension was used to assess the effect of macitentan (0.3-100 mg/kg/day orally for 4 weeks) on cardiac hypertrophy and survival [Iglarz et al 2008]. Both macitentan and bosentan dose-dependently prevented the development of pulmonary hypertension and, in addition, both drugs prevented the development of right ventricle hypertrophy, with maximal effective doses of 30 mg/kg for macitentan and 300 mg/ kg for bosentan.…”

Role of Notch Signaling in Pulmonary Hypertension

“…A novel, highly potent, tissue--targeting ERA, Macitentan characterized by high lipophilicity is under investigation [71].…”