Pharmacologic characterization of the novel, orally available endothelin-A-selective antagonist SB 247083

Competition radioligand binding with [I-125]ET-1 at human cloned ETA and ETB receptors demonstrated ET-(A) selective affinity by SB 247083 (K-i 0.41 and 467 nM, respectively). Accordingly, similar competitive, functional ETA receptor antagonism was observed. In vitro, SB 247083 exhibited a K-b of 3.5 +/- 0.3 nM (ET-1-induced rat aortic contraction). SB 247083 was significantly less potent as a functional ETB antagonist (K-b 0.34 +/- 0.01 muM; S6c-induced rabbit pulmonary artery contraction). In contrast to ETB-selective and mixed ETA/B antagonists, and consistent with its ETA-elective profile, in vivo administration of SB 247083 was not associated with an elevation in plasma ET-1 levels. Pharmacodynamic and pharmacokinetic studies revealed that SB 247083 was effectively absorbed from the gastrointestinal tract. A single bolus dose inhibited the hemodynamic actions of ET-1 for up to 8 h, consistent with a molecule shown to be 46% bioavailable. Therefore, the present study demonstrates that SB 247083, a unique chemical entity, represents a potent class of nonpeptide, orally active ETA-selective antagonists.