Macitentan is an antagonist of endothelin receptor A (ETA) with IC50 of 0.5 nM. It is developed for treatment of pulmonary arterial hypertension (PAH).
G protein-coupled receptor (GPCR) agonists through their receptors can transactivate protein tyrosine kinase receptors such as epidermal growth factor receptor and serine/threonine kinase receptors most notably transforming growth factor (TGF)-β receptor (TβRI).Several GPCR agonists such as Ang II, thrombin, ET-1 can mediate the transactivation of a multitude of protein tyrosine kinase receptors[5]. The three structurally closely related peptides, named endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3), are among the most potent vasoconstrictors known in humans. They convey their action through binding to two G-protein
coupled receptors called ETA and ETB. Among the three isopeptides, ET-1 appears to be the key player in the cardiovascular system. ET-2 and ET-3 are specifically expressed in the gastrointestinal tract and the brain, respectively. Macitentan is a dual ETA/ETB receptors antagonist designed through a deliberate discovery process to maximize endothelin-axis blockade while improving adverse-effect profiles with IC50 of 0.5 nM and 391 nM for ETA and ETB, respectively. Macitentan is a dual endothelin receptor antagonist (ERA) approved for the treatment of pulmonary arterial hypertension (PAH). The physicochemical properties of macitentan favor penetration into lung tissue, where macitentan predominantly exerts its effects. Macitentan is highly bound to plasma proteins. In a vivo experiment, Macitentan treatment at 1 mg/kg/day for five consecutive days stably reduced mean arterial blood pressure by -20 mmHg over the whole treatment period and made it returned to baseline about 48h after the last dose was given in Dahl salt-sensitive rats[4].
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