title: Pharmacological characterization of YM598, an orally active and highly potent selective endothelin ET(A) receptor antagonist.
abstract: We describe here the pharmacology of (E)-N-[6-methoxy-5-(2-methoxyphenoxy)[2,2'-bipyrimidin]-4-yl]-2-phenylethenesulfonamide monopotassium salt (YM598), a novel selective endothelin ET(A) receptor antagonist synthesized through the modification of the ET(A)/ET(B) non-selective antagonist, bosentan. YM598 inhibited [125I]endothelin-1 binding to cloned human endothelin ET(A) and ET(B) receptor, with K(i) of 0.697 and 569 nM, and inhibited endothelin-1-induced increases in intracellular Ca(2+) concentration in human and rat endothelin ET(A) receptor. YM598 also inhibited endothelin-1-induced vasoconstriction in isolated rat aorta with a pA(2) value of 7.6. In vivo, YM598 inhibited the pressor response to big endothelin-1, a precursor peptide of endothelin-1. DR(2) values of YM598 in pithed rats were 0.53 mg/kg, i.v. and 0.77 mg/kg, p.o., and its antagonism in conscious rats was maintained for more than 6.5 h at 1 mg/kg, p.o. In contrast, YM598 had no effect on the sarafotoxin S6c-induced depressor or pressor responses. YM598 showed not only superior antagonistic activity and higher-selectivity for endothelin ET(A) receptor in vitro, but at least a 30-fold higher potency in vivo than bosentan. In conclusion, YM598 is a potent and orally active selective endothelin ET(A) receptor antagonist.
authors.affiliation: Pharmacology Laboratories Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co, Ltd, 21, Miyukigaoka, Ibaraki Tsukuba 305-8585, Japan. yuyama@yamamouchi.co.jp
authors.forename: Hironori
authors.initials: H
authors.lastname: Yuyama
authors.forename: Masanao
authors.initials: M
authors.lastname: Sanagi
authors.forename: Akiko
authors.initials: A
authors.lastname: Koakutsu
authors.forename: Mikiko
authors.initials: M
authors.lastname: Mori
authors.forename: Akira
authors.initials: A
authors.lastname: Fujimori
authors.forename: Hironori
authors.initials: H
authors.lastname: Harada
authors.forename: Katsumi
authors.initials: K
authors.lastname: Sudoh
authors.forename: Keiji
authors.initials: K
authors.lastname: Miyata
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists; D006801:Humans; D008297:Male; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D065130:Endothelin A Receptor Antagonists; C449179:N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D013449:Sulfonamides