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-fert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2, 2'-bipyrimidin-4-yl]-benzenesulfonamide) competitively antagonized the specific binding of [125I]-labeled ET-1 on human smooth muscle cells (ETAreceptors) with a KÃŒof 4.7 nM and on human placenta (ETBreceptors) with a K/of 95 nM. It also inhibited the binding of selective ETBligands on porcine trachea. Contractions induced by ET-1 in isolated rat aorta (ETA) and by the selective ETBagonist sarafotoxin S6C in rat trachea were competitively inhibited by bosentan (pA2= 7.2 and 6.0, respectively), as was the endothelium-dependent relax ation 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 bosen tan, which shows its specificity for ET receptors. In vivo, bos entan inhibited the presser response to big ET-1 both after iv and oral administration, with a long duration of action and no intrinsic agonist activity. It also inhibited the depressor and presser effect of ET-1 and sarafotoxin S6C. Thus, bosentan is the most potent orally active antagonist of ET receptors de scribed so far. Its pharmacological profile makes bosentan a potentially useful drug in the management of clinical disorders associated with vasoconstriction.

ET-1, besides its potent and prolonged vasoconstrictor effect, may exert various biological actions in rodents and other mammals. It plays a role in the regulation of water and electro lyte balance, in the modulation of secretion of a number of hormones, in cell proliferation and in vascular permeability (Miller et al, 1993; Rubanyi, 1992). So far, three ET receptor subtypes have been described. Arai