title: Pharmacologic characterization of S-1255, a highly potent and orally active endothelin A receptor antagonist.
abstract: 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. [3H]S-1255 specifically bound to porcine aortic smooth muscle membranes expressing only ET(A) receptors with a Kd value of 0.39 nM. [3H]S-1255 binding was potently inhibited by ET-1 and selective ET(A) or ET(A)/ET(B) receptor antagonists, such as L-749329, SB209670, bosentan, and BQ-123, but the inhibitory effect of ET-3 and the selective ET(B) receptor antagonist, BQ-788, on the binding was weak. These inhibitory effects on [3H]S-1255 binding correlated well with those on [125I]ET-1 binding. S-1255 inhibited ET(A) receptor- and ET(B) receptor-mediated contractions in isolated rabbit femoral and pulmonary arteries with pA2 values of 8.8 and 6.3, respectively. The pA2 value of S-1255 for ET(B) 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 pressor 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 ET(A) receptor antagonist.
authors: Discovery Research Laboratories, Shionogi & Co., Ltd., Toyonaka, Osaka, Japan.
authors: T
authors: T
authors: Iwasaki
authors: S
authors: S
authors: Mihara
authors: T
authors: T
authors: Shimamura
authors: M
authors: M
authors: Kawakami
authors: M
authors: M
authors: Masui
authors: Y
authors: Y
authors: Hayasaki-Kajiwara
authors: N
authors: N
authors: Naya
authors: M
authors: M
authors: Ninomiya
authors: M
authors: M
authors: Fujimoto
authors: M
authors: M
authors: Nakajima
mesh_terms: D000818:Animals; D001011:Aorta; D001578:Benzopyrans / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D016466:CHO Cells; D006224:Cricetinae; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D013552:Swine; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: C436483:2-(benzo(1,3)dioxo-5-yl)-6-isopropyl-4-(4-methoxyphenyl)-2H-chromene-3-carboxylic acid; D001578:Benzopyrans; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D044022:Receptor, Endothelin A; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6