Potent and selective ET-A antagonists. 1. Syntheses and structure-activityrelationships of N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives

Modifications to the ETA/B mixed type compounds 1 (Ro. 46-2005) and 2 (bose ntan) were performed. Introduction of a pyrimidine group into 1 resulted in a dramatic increase in affinity for the ETA receptor, and the subsequent o ptimization of substituents on the pyrimidine ring led us to the discovery of N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)-4pyrimidi nyl)-4-tert-butylbenzenesulfonamide (7k), which showed an extremely high af finity for the human cloned ETA receptor (K-i = 0.0042 +/-0.0038 nM) and an ETA/B receptor selectivity up to 29 000 (K-i = 130 +/- 50 nM for the human cloned ETB receptor). The compound was designed on the hypothesis that the hydrogen atom of the hydroxyl group in 1 and 2 played a role not as a prot on donor but as an acceptor in the possible hydrogen bonding with Tyr129. S ince the incorporation of a pyrimidinyl group into the hydroxyethoxy side c hain of the nonselective antagonist (1) dramatically enhanced both the ETA receptor affinity and selectivity, and since similar results were obtained from the benzene analogues, we put forward the hypothesis that a "pyrimidin e binding pocket" might exist in the ETA receptor.