Bosentan (hydrate)

Bosentan hydrate is a competitive and dual antagonist of endothelin-1 (ET) for the ET_A and ET_B receptors with K_i of 4.7 nM and 95 nM in human SMC, respectively. IC50 & Target: Ki: 4.7 nM (ET_A receptor, in human SMC), 95 nM (ET_A receptor, in human SMC)^[1] In Vitro: Bosentan (BOS) competitively and specifically antagonizes binding of ¹²⁵I-labelled ET-1 to ET_A receptors on human smooth muscle cells (SMC) and ET_B receptors on human placenta cells. The in vitro binding affinity of Bosentan to ET_A receptors on human SMC is 4.7 nM and to ET_B receptors on human SMC or placenta cells is 41 or 95 nM. Bosentan has 67-fold greater selectivity for ET_A than ET_B receptors (mean IC₅₀=7.1 vs 474.8 nM) in an in vitro ¹²⁵I-labeling assay^[1]. In Vivo: Single-dose Bosentan 62.5 mg significantly (p<0.01 vs baseline) plasma ET-1 levels by 2-fold in 7 pts with WHO class II or III idiopathic or CTD-associated PAH, with peak levels achieved at 8 h^[1]. In hypertensive rats, Macitentan 30 mg/kg further decreases mean arterial blood pressure (MAP) by 19 mm Hg when given on top of Bosentan 100 mg/kg. Conversely, Bosentan given on top of Macitentan fails to induce an additional MAP decrease. In pulmonary hypertensive rats, Macitentan 30 mg/kg further decreases mean pulmonary artery pressure (MPAP) by 4 mm Hg on top of Bosentan, whereas a maximal effective dose of Bosentan given on top of Macitentan does not cause any additional MPAP decrease^[3].