The endothelins (ETs), potent vasoconstrictor peptides, have been implicated in the pathogenesis of various cardiovascular disorders. In the present study, we describe the novel, potent, orally active, selective ET(A) receptor antagonist ZD1611 [3-(4-[3-(3-methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyridyl ]phenyl)- 2,2-dimethylpropanoic acid]. ZD1611 competitively inhibited (125)I-labeled ET-1 binding at human cloned ET(A) and ET(B) receptors with pIC(50) values of 8.6 +/- 0.1 and 5.6 +/- 0.1, respectively, showing 1000-fold selectivity for the ET(A) receptor. ZD1611 caused a parallel rightward shift of the concentration response curve to ET-1 in the rat isolated aorta yielding a concentration of antagonist that caused a 2-fold rightward shift in the ET-1-response curve (pA(2)) of 7.5 +/- 0.3. When administered i. v. to anesthetized rats and dogs, ZD1611 caused dose-related rightward shifts of partial dose-response curves to the precursor of ET-1, big ET-1. Threshold doses for significant antagonist activity were determined as 0.1 mg/kg and 0.3 mg/kg in the rat and dog, respectively. Importantly, ZD1611 was able to reverse an established big ET-1-induced pressor response in pithed rats in the presence of continuous big ET-1 infusion. Failure of ZD1611 to inhibit the BQ3020 (ET(B)-selective)-induced depressor response in pithed rats indicated a lack of activity at the endothelial ET(B) receptor. ZD1611 was orally active in the rat at 0.3 mg/kg and had a duration of action of more than 7 h, and, in the dog, a dose of 0.6 mg/kg p.o. was active for at least 6 h. In conclusion, these data demonstrate that ZD1611 is a potent and orally active, selective ET(A) receptor antagonist with a long duration of action which may be of therapeutic use.