Pharmacological characterization of YM598, an orally active and highly potent selective endothelin ETA receptor antagonist

Abstract We describe here the pharmacology of ( E )- N -[6-methoxy-5-(2-methoxyphenoxy)[2,2′-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), a novel selective endothelin ET A receptor antagonist synthesized through the modification of the ET A /ET B non-selective antagonist, bosentan. YM598 inhibited [ 125 I]endothelin-1 binding to cloned human endothelin ET A and ET B receptor, with K i of 0.697 and 569 nM, and inhibited endothelin-1-induced increases in intracellular Ca 2+ concentration in human and rat endothelin ET A receptor. YM598 also inhibited endothelin-1-induced vasoconstriction in isolated rat aorta with a p A 2 value of 7.6. In vivo, YM598 inhibited the pressor response to big endothelin-1, a precursor peptide of endothelin-1. DR 2 values of YM598 in pithed rats were 0.53 mg/kg, i.v. and 0.77 mg/kg, p.o., and its antagonism in conscious rats was maintained for more than 6.5 h at 1 mg/kg, p.o. In contrast, YM598 had no effect on the sarafotoxin S6c-induced depressor or pressor responses. YM598 showed not only superior antagonistic activity and higher-selectivity for endothelin ET A receptor in vitro, but at least a 30-fold higher potency in vivo than bosentan. In conclusion, YM598 is a potent and orally active selective endothelin ET A receptor antagonist.