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-activi ty relationship of a potent and selective ETA receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ETA receptor a ntagonist activity were identified. This study suggested the metabolic path ways of 1 were considerably affected by species. Consequently, structural m odification of 1 intended to improve the complexity of the metabolic pathwa y, and water solubility was performed. The subsequent introduction of a hyd roxyl 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 (K-i for ETA receptor: 0.015 +/-0.004 nM; for ETB r eceptor: 41 +/- 21 nM).