Pharmacologic characterization of S-1255, a highly potent and orally active endothelin A receptor antagonist

The pharmacologic properties of a novel nonpeptide endothelin (ET) receptor antagonist, S-1255 ([R]-[+]-2-[benzo(1,3)dioxol-5-yl]-6-isopropyl-4- [4-methoxyphenyl]-2H-chromene-3-carboxylic acid), was studied. [H-3]S-1255 specifically bound to porcine aortic smooth muscle membranes expressing only ETA receptors with a K-d value of 0.39 nM. [H-3]S-1255 binding was potently inhibited by ET-1 and selective ETA or ETA/ETB receptor antagonists, such as L-749329, SB209670, bosentan, and BQ-123, but the inhibitory effect of ET-3 and the selective ETB receptor antagonist, BQ-788, on the binding was weak. These inhibitory effects on [H-3]S-1255 binding correlated well with those on [I-125]ET-1 binding. S-1255 inhibited ETA receptor- and ETA receptor-mediated contractions in isolated rabbit femoral and pulmonary arteries with pA(2) values of 8.8 and 6.3, respectively. The pA(2) value of S-1255 for ETA receptor-mediated relaxation in isolated rabbit mesenteric artery was 7.4. Oral administration of S-1255 (0.3-10 mg/kg) caused dose-dependent inhibition of the presser response to exogenous ET-1 (0.1 nmol/kg) in conscious normotensive rats, which was similar to that produced by intravenous administration (1 and 3 mg/kg). S-1255 (10 and 30 mg/kg, p.o,) significantly reduced blood pressure in deoxycorticosterone acetate-salt hypertensive rats from 6 h after administration, and the hypotensive effects were sustained up to 24-48 h. These results suggest that S-1255 is a highly potent and orally active ETA receptor antagonist.