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M Clozel, V Breu, GA Gray, B Kalina, BM Loffler, K Burri, JM Cassal, G Hirth, M Muller and W Neidhart
F. Hoffmann-La Roche Ltd., Basel, Switzerland.
The authors describe here the pharmacological properties of bosentan, a new nonpeptide mixed antagonist of endothelin (ET) receptors, obtained by structural optimization of the less potent Ro 46-2005 [Ro 46-2005 (4- tert-butyl-N-[6-(2-hydroxyethoxy)-5-(3-methoxy-phenoxy)-4-pyrimidinyl ]- benzenesulfonamide]. Bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2-hydroxy- ethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyr imidin-4-yl]- benzenesulfonamide) competitively antagonized the specific binding of [125I]-labeled ET-1 on human smooth muscle cells (ETA receptors) with a Ki of 4.7 nM and on human placenta (ETB receptors) with a Ki of 95 nM. It also inhibited the binding of selective ETB ligands on porcine trachea. Contractions induced by ET-1 in isolated rat aorta (ETA) and by the selective ETB agonist sarafotoxin S6C in rat trachea were competitively inhibited by bosentan (pA2 = 7.2 and 6.0, respectively), as was the endothelium-dependent relaxation to sarafotoxin S6C in rabbit superior mesenteric artery (pA2 = 6.7). The binding of 40 other peptides, prostaglandins, ions and neurotransmitters was not significantly affected by bosentan, which shows its specificity for ET receptors. In vivo, bosentan inhibited the pressor response to big ET-1 both after i.v. and oral administration, with a long duration of action and no intrinsic agonist activity. It also inhibited the depressor and pressor effect of ET-1 and sarafotoxin S6C. Thus, bosentan is the most potent orally active antagonist of ET receptors described so far. Its pharmacological profile makes bosentan a potentially useful drug in the management of clinical disorders associated with vasoconstriction.
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