PHARMACOLOGICAL CHARACTERIZATION OF BOSENTAN, A NEW POTENT ORALLY-ACTIVE NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONIST

The authors describe here the pharmacological properties of bosentan, a new nonpeptide mixed antagonist of endothelin (ET) receptors, obtain ed by structural optimization of the less potent Ro 46-2005 [Ro 46-200 5 thoxy-phenoxy)-4-pyrimidinyl]-benzenesulfonamide]. Bosentan (Ro 47-0 203, hoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-benzenesulfo- namide) compet itively antagonized the specific binding of [I-125]- labeled ET-1 on h uman smooth muscle cells (ET(A) receptors) with a K-I of 4.7 nM and on human placenta (ET(B) receptors) with a K-I of 95 nM. It also inhibit ed the binding of selective ET(B) ligands on porcine trachea. Contract ions induced by ET-1 in isolated rat aorta (ET(A)) and by the selectiv e ET(B) agonist sarafotoxin S6C in rat trachea were competitively inhi bited by bosentan (pA(2) = 7.2 and 6.0, respectively), as was the endo thelium-dependent relaxation to sarafotoxin S6C in rabbit superior mes enteric artery (pA(2) = 6.7). The binding of 40 other peptides, prosta glandins, ions and neurotransmitters was not significantly affected by bosentan, which shows its specificity for ET receptors. In vivo, bose ntan inhibited the presser response to big ET-1 both after i.v. and or al administration, with a long duration of action and no intrinsic ago nist activity. It also inhibited the depressor and presser effect of E T-1 and sarafotoxin S6C. Thus, bosentan is the most potent orally acti ve antagonist of ET receptors described so far. Its pharmacological pr ofile makes bosentan a potentially useful drug in the management of cl inical disorders associated with vasoconstriction.