title: Superiority of YM598 over atrasentan as a selective endothelin ETA receptor antagonist.
abstract: The binding affinities of (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598) for native human endothelin ETA and ETB receptors expressed in human coronary artery smooth muscle cells (CASMC) and a human melanoma cell line, SK-Mel-28, respectively, were examined, and the results compared with those for the endothelin receptor antagonists atrasentan and bosentan. The in vivo endothelin ETA receptor inhibitory activities of YM598 and atrasentan were also compared through the suppression of the big endothelin-1-induced pressor response in pithed rats. Ki values of YM598, atrasentan, and bosentan for native human endothelin ETA receptors were 0.772, 0.0551, and 4.75 nM, while those for native human endothelin ETB receptors were 143, 4.80, and 40.9 nM, respectively. The calculated selectivity ratios of YM598, atrasentan, and bosentan for endothelin ETA versus ETB receptors were 185, 87 and 8.6, respectively. In pithed rats, YM598 and atrasentan inhibited the big endothelin-1 (1 nmol/kg)-induced pressor response in a dose-dependent manner on both intravenous and oral administration. The inhibitory effect of YM598 was less potent than that of atrasentan when these agents were intravenously administered, but closely similar on oral administration. These results suggest that YM598 has high selectivity for native human ETA against ETB receptors, and that YM598 is superior to atrasentan as an ETA receptor antagonist with regard to pharmacological bioavailability in rats.
authors.affiliation: Applied Pharmacology Research, Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
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: Noriko
authors.initials: N
authors.lastname: Fujiyasu
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Ohtake
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.forename: Katsumi
authors.initials: K
authors.lastname: Sudoh
authors.forename: Masao
authors.initials: M
authors.lastname: Sasamata
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyata
mesh_terms: D000077868:Atrasentan; D001667:Binding, Competitive / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007457:Iodine Radioisotopes; D009842:Oligopeptides / Q000378:metabolism / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D011759:Pyrrolidines / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D044022:Receptor, Endothelin A / Q000819:agonists / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000819:agonists / Q000378:metabolism; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014757:Viper Venoms / Q000378:metabolism / Q000494:pharmacology
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D007457:Iodine Radioisotopes; 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; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D000077868:Atrasentan