Macitentan

Macitentan is a pivotal pharmaceutical API and analytical reference standard in the treatment of pulmonary arterial hypertension, functioning as a tissue-targeting dual ETA/ETB endothelin receptor antagonist. As a dual antagonist, Macitentan binds to both endothelin A and B receptors and blocks signaling from endothelin-1 and -2, thereby reducing vasoconstriction and cell proliferation due to endothelin overexpression. Macitentan prevents endothelin-1 from causing vasoconstriction and vascular remodeling, which are key contributors to PAH. Macitentan has the potential for idiopathic pulmonary fibrosis (IPF) and pulmonary arterial hypertension, and has demonstrated efficacy in reducing arterial blood pressure in hypertensive animal models at concentrations 10-fold lower than bosentan. Macitentan has a molecular weight of 588.27 g/mol and appears as a white to off-white powder.

 

Product Parameters

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Parameter	Specification
Product Name	Macitentan
CAS Number	441798-33-0
Molecular Formula	C₁₉H₂₀Br₂N₆O₄S
Molecular Weight	588.27 g/mol
Appearance	White to off-white powder
Boiling Point	692.4 ± 65.0 °C (Predicted)
Density	1.675
pKa	4.99 ± 0.50 (Predicted)
Storage Condition	Store at –20 °C

 

Pharmacological Action

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        Macitentan is a novel oral dual endothelin receptor antagonist targeting both ETRA and ETRB. In vivo, mecitidine is primarily metabolized by CYP3A4 into the active metabolite ACT-132577, both of which exhibit biological activity by inhibiting the binding of ET-1 to ETA and ETB receptors. An in vitro receptor selection and functional blocking assay demonstrated that the IC50 values of mecitidine for ETA and ETB were (0.5 ± 0.2) nmol·L⁻¹ (n = 17) and (391 ± 182) nmol·L⁻¹ (n = 17), respectively; whereas those of ACT-132577 were (3.4 ± 0.4) nmol·L⁻¹ (n = 4) and (987 ± 185) nmol·L⁻¹ (n = 9). Both mecitidine and ACT-132577 effectively inhibit the binding of ET-1 to ETA and ETB receptors, thereby preventing ET-1-induced intracellular calcium elevation and vasoconstriction.

In DOCA (deoxycorticosterone acetate)-induced hypertensive rats, a single dose of 10 mg masititan reduced arterial blood pressure by 26 ± 4 mmHg, while a single dose of 100 mg bosentan reduced it by 20 ± 5 mmHg; neither agent affected heart rate. Macitentan achieved equivalent or even superior antihypertensive effects at concentrations up to 10 times lower than those required for bosentan, with a duration of action twice as long as that of bosentan, demonstrating superior pharmacological activity.

 

Pharmacokinetics

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After oral administration, Macitentan is metabolized by CYP3A4, yielding the primary metabolites ACT-132577 and ACT-373898, which are ultimately excreted via feces and urine, with urinary excretion being the predominant route. In healthy male volunteers administered a single dose of 10 mg Macitentan, the peak plasma concentration (Tmax) averaged 8–10 hours, with a half-life (t1/2) of 13 hours. The active metabolite ACT-132577 exhibited an average Tmax of 48 hours and a t1/2 of 44 hours. Plasma concentrations of both Macitentan and ACT-132577 were generally lower in patients with varying degrees of hepatic impairment compared to healthy subjects; however, no clinically significant differences were observed during the study, and no dosage adjustment is required for patients with hepatic impairment of any severity.

Drug Component

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Marixetan tablets contain excipients such as lactose, microcrystalline cellulose (MCC), sodium carboxymethyl starch (CMS-Na), polyvinylpyrrolidone (PVP) K30, magnesium stearate, and Tween-80.

Contact Us

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Interested in Macitentan for your PAH API program, impurity reference standard needs, or receptor pharmacology research? Cosperpharm is here to assist. Reach out to our team today for a quote, technical support, or regulatory documentation.