Pharmacological characterization of YM598, a selective endothelin-A receptor antagonist.
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.
Sudoh
Katsumi
K
Pharmacology Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Tsukuba-shi, Ibaraki, Japan. sudoh@yamanouchi.co.jp
Yuyama
Hironori
H
Noguchi
Yukiko
Y
Fujimori
Akira
A
Ukai
Masashi
M
Ohtake
Akiyoshi
A
Sato
Shuichi
S
Sasamata
Masao
M
Miyata
Keiji
K
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
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