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 ETA receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ETA receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 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 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ETA receptor (Ki for ETA receptor:  0.015 ± 0.004 nM; for ETB receptor:  41 ± 21 nM).