title: Pharmacological characterization of YM598, a selective endothelin-A receptor antagonist.
abstract: The binding affinities of YM598, a novel endothelin-A (ETA) receptor antagonist, for native human ETA receptors expressed in human coronary artery smooth muscle cells and endothelin-B (ETB) subtypes in the human melanoma cell line SKMel- 28 were compared with those of atrasentan and bosentan. The in vivo ETA receptor antagonist activities of YM598 and atrasentan were also evaluated in pithed rats. The inhibitory dissociation constant values of YM598, atrasentan and bosentan were 0.772, 0.0551 and 4.75 nM, respectively, for native human ETA receptors, and 143, 4.80 and 40.9 nM, respectively, for native human ETB subtypes. The calculated selectivity ratios of YM598, atrasentan and bosentan for ETA versus ETB receptors were 222, 136 and 13.0, respectively. In pithed rats, YM598 and atrasentan inhibited the big endothelin-1 (1 nmol/kg)-induced pressor response in a dose-dependent manner, after both intravenous and oral administration. The inhibitory effect of YM598 was less potent than that of atrasentan when these agents were intravenously administered, but those of both agents were comparable when orally administered. These results suggest that YM598 has a high selectivity for native human ETA receptors against ETB receptors, and that YM598 is superior to atrasentan as an ETA receptor antagonist, with regard to pharmacological bioavailability in rats.
authors.affiliation: Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Tsukuba-shi, Ibaraki, Japan. sudoh@yamanouchi.co.jp
authors.forename: Katsumi
authors.initials: K
authors.lastname: Sudoh
authors.forename: Hironori
authors.initials: H
authors.lastname: Yuyama
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Noguchi
authors.forename: Akira
authors.initials: A
authors.lastname: Fujimori
authors.forename: Masashi
authors.initials: M
authors.lastname: Ukai
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ohtake
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000077868:Atrasentan; D001667:Binding, Competitive; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000378:metabolism; D010456:Peptides, Cyclic / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D014757:Viper Venoms / Q000378:metabolism
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; C449179:N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D011743:Pyrimidines; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D014757:Viper Venoms; C057354:sarafotoxins s6; C086539:BQ 788; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D000077868:Atrasentan