title: Modifications and structure-activity relationships at the 2-position of 4-sulfonamidopyrimidine derivatives as potent endothelin antagonists.
abstract: To improve water solubility and to study structure-activity relationships, we modified the structure of the pyrimidine nucleus of each of a series of potent ET(A) antagonists, 3a and 4a, at the 2-position. In a previous study, each of these antagonists showed an extremely high affinity for the ET(A) receptor in porcine aortic membrane (IC(50) 3a; < 0.001 nM, 4a; 0.0039 nM). Two modification methods, one being the addition of organolithium followed by DDQ oxidation and the other being the nucleophilic substitution of 2-(methylsulfonyl)pyrimidine, were applied individually to synthesize 2-substituted-4-sulfonamidopyrimidine derivatives. The introduction of aryl, heteroaryl, alkyl, amino, alkoxy, or alkylthio groups into the 2-position varied the affinity. Derivatives with hydrophilic groups at the 2-position showed higher water solubility but tended to reduce the affinity for the ET(A) receptor.
authors.affiliation: Discovery Research Laboratory, Tanabe Seiyaku Co. Ltd., 2-2-50 Kawagishi, Toda, 335-8505, Saitama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Morimoto
authors.forename: Hideshi
authors.initials: H
authors.lastname: Shimadzu
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hosaka
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawase
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yasuda
authors.forename: Kohei
authors.initials: K
authors.lastname: Kikkawa
authors.forename: Rikako
authors.initials: R
authors.lastname: Yamauchi-Kohno
authors.forename: Koichiro
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000818:Animals; D001011:Aorta; D001667:Binding, Competitive; D004353:Drug Evaluation, Preclinical; D016232:Endothelins / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013552:Swine
chemical_list: D016232:Endothelins; D011743:Pyrimidines; D013449:Sulfonamides