Pharmacological profile of ZD1611, a novel, orally active endothelin ETA receptor antagonist

The endothelins (ETs), potent vasoconstrictor peptides, have been implicate d in the pathogenesis of various cardiovascular disorders. In the present s tudy, we describe the novel, potent, orally active, selective ETA receptor antagonist ZD1611 [3-(4-[3-(3- methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyr idyl]phenyl)-2,2-dimethylpropanoic acid]. ZD1611 competitively inhibited I- 125-labeled ET-1 binding at human cloned ETA and ETB receptors with pIC(50) values of 8.6 +/- 0.1 and 5.6 +/- 0.1, respectively, showing 1000-fold sel ectivity for the ETA 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 anest hetized rats and dogs, ZD1611 caused dose-related rightward shifts of parti al 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 m g/kg in the rat and dog, respectively. Importantly, ZD1611 was able to reve rse an established big ET-l-induced presser response in pithed rats in the presence of continuous big ET-1 infusion. Failure of ZD1611 to inhibit the BQ3020 (ETB selective)-induced depressor response in pithed rats indicated alack of activity at the endothelial ET, 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 conc lusion, these data demonstrate that ZD1611 is a potent and orally active, s elective ETA receptor antagonist with a long duration of action which may b e of therapeutic use.