title: Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.
abstract: In the previous paper, we described a series of 2-phenylethenesulfonamide derivatives, a novel class of ET(A)-selective endothelin (ET) receptor antagonists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy derivative (2b). In this paper, we wish to report further details of structure-activity relationships (SARs) of the two regions of the molecule in compound 2b, which were the alkoxy region at the 6-position of the core pyrimidine ring and the 2-phenylethenesulfonamide region. In these modifications, replacement of the 2-fluoroethoxy group with a methoxy group (6e) and replacement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenesulfonamide group (6l) or 2-phenylethanesulfonamide group (6q) were well tolerated both in the ET(A) binding affinity and ET(A) selectivity. Among them, compound 6e showed further improvement in oral activity compared to 2b. After oral administration, compound 6e inhibited the big ET-1 induced pressor response in conscious rats at 0.3mg /kg with a duration of >6.5h. Compound 6e also exhibited a potent antagonistic activity in the pithed rats.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21Miyukigaoka, Tsukuba, 305-8585, Ibaraki, Japan. haradah@yamanouchi.co.jp
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.forename: J
authors.initials: J
authors.lastname: Kazami
authors.forename: S
authors.initials: S
authors.lastname: Watanuki
authors.forename: R
authors.initials: R
authors.lastname: Tsuzuki
authors.forename: K
authors.initials: K
authors.lastname: Sudoh
authors.forename: A
authors.initials: A
authors.lastname: Fujimori
authors.forename: M
authors.initials: M
authors.lastname: Sanagi
authors.forename: M
authors.initials: M
authors.lastname: Orita
authors.forename: H
authors.initials: H
authors.lastname: Nakahara
authors.forename: J
authors.initials: J
authors.lastname: Shimaya
authors.forename: S
authors.initials: S
authors.lastname: Tsukamoto
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
authors.forename: I
authors.initials: I
authors.lastname: Yanagisawa
mesh_terms: D000284:Administration, Oral; D000476:Alkanesulfonates / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001667:Binding, Competitive; D001794:Blood Pressure / Q000187:drug effects; D019556:COS Cells; D018360:Crystallography, X-Ray; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000476:Alkanesulfonates; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; C449179:N-(6-methoxy-5-(2-methoxyphenoxy)-2-(pyrimidin-2-yl)pyrimidin-4-yl)-2-phenylethenesulfonamide; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D013449:Sulfonamides; C002634:ethane sulfonate