Potent and Selective ET-A Antagonists. 2. Discovery and Evaluation of Potent and Water Soluble N-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives

In the preceding article,¹ we outlined the discovery and structure−activity relationship of a potent and selective ET<INF>A</INF> receptor antagonist <BO>1</BO> and its related compounds. Metabolites of <BO>1</BO> having potent selective ET<INF>A</INF> receptor antagonist activity were identified. This study suggested the metabolic pathways of <BO>1</BO> were considerably affected by species. Consequently, structural modification of <BO>1</BO> intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of <BO>1</BO> led to the discovery of our new clinical candidate, <BO>6b</BO>, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ET<INF>A</INF> receptor (K<INF>i</INF> for ET<INF>A</INF> receptor:  0.015 ± 0.004 nM; for ET<INF>B</INF> receptor:  41 ± 21 nM).