Macitentan (ACT 064992)

InformationMacitentan (ACT 064992) Macitentan (ACT 064992) is an orally active, non-peptide, dual ETA/ETB (endothelin) receptor antagonist with IC50 of 0.5 nM/391 nM.In vitroMacitentan achieves full inhibition of intracellular calcium increase induced by ET-1 on primary human pulmonary smooth muscle cells with approximate IC50 of 1 nM. Macitentan inhibits 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 vivoMacitentan administered to normotensive rats, increases plasma ET-1 concentration, which occurred at a 10-fold lower dose than with bosentan. Macitentan dose-dependently decreases mean arterial blood pressure in hypertensive DOCA-salt rats with a maximal effect of -26 mm Hg at a dose of 10 mg/kg and a ED50 of 1mg/kg. At the maximal effective dose, the duration of the blood pressure response to Macitentan is approximately 40 hr. Macitentan orally administrated dose-dependently preventes 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 improves the 42-day survival in monocrotaline rats (83 vs 50% survival in macitentan vs vehicle; 66% reduction of mortality at 42 days). Macitentan (30 mg/kg/day) treated for 24 h partially prevents the development of renal vasoconstriction and increases renal blood flow in streptozotocin-induced diabetic rat model. Macitentan increases glomerular filtration rate and decreases filtration fraction, and attenuates vascular and tubulo-interstitial lesions and also glomerular damage. Macitentan (25 mg/kg/day, p.o.) attenuates the increase of renal, cardiac and retinal ET-1, TGF-β1, VEGF, FN, EDB+FN, collagenα-I(IV) mRNA expression along with increased FN, collagen protein and NF-κB activation induced by type 2 diabetes in db/db mice. Macitentan also ameliorates mesangial expansion, cardiac dysfunction and the increased expression of ANP and BNP in these diabetic mice. Macitentan (100mg/kg) treatment combined with paclitaxel (5 mg/kg) reduced tumor incidence (5/9 vs 9/9 of paclitaxel along) and further reduces tumor weight (median [range]: 0.1 vs 0.4 g of paclitaxel along) and incidences of ascites (0/9 vs 4/9 of paclitaxel along) in SKOV3ip1 ovarian cancer model when compared with paclitaxel alone. Macitentan plus paclitaxel inhibits the phosphorylation of ETRs and suppresses the survival pathways of tumor cells by decreasing the levels of pVEGFR2, pAkt, and pMAPK. Macitentan enhances effects of paclitaxel on tumor cells dividing (Brud+ cells: 18.5 vs 30.8 of paclitaxel along) and apoptosis (TUNEL+ cells: 195 vs 150 of paclitaxel along).Cell Datacell lines：Concentrations：Incubation Time：Powder Purity:≥97%. Specification: 10mM in DMSO Molecular Formula: C19H20Br2N6O4S Molecular Weight: 588.27