Cell lines

Primary human pulmonary smooth muscle cells, microvascular endothelial cells

Preparation method

The solubility of this compound in DMSO is >21.2 mg/mL. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months.

Reacting condition

IC50: 1 nM

Applications

Macitentan completely inhibited intracellular calcium increase induced by ET-1 on primary human pulmonary smooth muscle cells with approximate IC50 of 1 nM. Macitentan inhibited ET-1-induced contractions on isolated rat aortic rings or S6c-induced contractions on isolated rat tracheal rings with pA2 of 7.6 and 5.9, respectively. In microvascular endothelial cells, pretreatment with macitentan restored tube formation ability and reduced the expression of mesenchymal markers and restored CD31 expression and the imbalance between VEGF-A and VEGF-A165b.

Animal models

Hypertensive DOCA-salt rats, monocrotaline rat model of pulmonary hypertension, SKOV3ip1 ovarian cancer model

Dosage form

Oral administration, 25 mg/kg/day

Application

In normotensive rats, macitentan increased plasma ET-1 concentration. Macitentan dose-dependently decreased mean arterial blood pressure in hypertensive DOCA-salt rats with a maximal effect of -26 mm Hg at a dose of 10 mg/kg. Oral administration of macitentan dose-dependently prevented the development of pulmonary hypertension and the development of right ventricle hypertrophy with a maximal efficacy of 30 mg/kg/day in monocrotaline rat model of pulmonary hypertension. Chronic oral administration of macitentan at 30 mg/kg/day significantly improved the 42-day survival in monocrotaline rats. Macitentan (25 mg/kg/day, p.o.) prevented increased production of vasoactive and fibrogenic factors, NF-κB activation, structural and functional changes, and increased extracellular matrix protein production in type 2 diabetes. Macitentan (10 mg/kg, p.o.) in combination with once-per-week 5 mg/kg taxol significantly reduced the weight (size) of HeyA8-MDR tumors in mice. Combination therapy with macitentan (10 or 50 mg/kg) and taxol or macitentan (10 mg/kg) and cisplatinum significantly reduced the number of proliferating Ki-67-positive cells. Macitentan (100 mg/kg) treatment combined with paclitaxel (5 mg/kg) reduced tumor incidence and further reduced tumor weight and incidences of ascites in SKOV3ip1 ovarian cancer model. Macitentan plus paclitaxel inhibited the phosphorylation of ETRs and suppressed the survival pathways of tumor cells by decreasing the levels of pVEGFR2, pAkt, and pMAPK. Macitentan enhanced effects of paclitaxel on tumor cells dividing and apoptosis.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

Macitentan is a new dual ETA/ETB endothelin (ET) receptor antagonist, with mean IC50 values of 0.5 ± 0.2 nM (n= 17) to inhibit the binding of 125I-ET-1 to recombinant ETA receptors, and of 391±182 nM (n= 17) for ETB receptors in Chinese hamster ovary cells [1].

ETA and ETB are ET receptors, both of them mediate the detrimental actions of ET-1, and dual blockade of them may be necessary [1].

In microsomal membranes of human-ETA and ETB-overexpressing Chinese hamster ovary cells, macitentan inhibited the binding between 125I-ET-1 and recombinant ETA receptors, with a mean IC50 value of 0.5 ± 0.2 nM (n= 17). The mean IC50 value for ETB receptors was 391±182 nM (n= 17). Macitentan completely inhibited the effect that ET-1 increased intracellular calcium in non-recombinant cells [1].

Intravenous administrated macitentan had a volume of distribution largely exceeding plasma volume and a terminal half-life of 2 h in rats. Macitentan was hence metabolized to its major and the only circulating metabolite, a dual ET receptor antagonist, ACT-132577. ACT-132577 also had a volume of distribution greater than the plasma volume. It showed a longer half-life than macitentan in rats. In rat, multiple oral dosing of macitentan at a dose of 10 mg/kg led to 4 to 5-fold higher exposure levels of ACT-132577 than those of the parent compound [1].

Reference:
[1]. Marc Iglarz, Christoph Binkert, Keith Morrison, et al. Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist. Journal of Pharmacology and Experimental Therapeutics, 2008, 327:736-745.