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 ; 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.