Biphenylsulfonamide Endothelin Receptor Antagonists. 2. Discovery of 4‘-Oxazolyl Biphenylsulfonamides as a New Class of Potent, Highly Selective ETA Antagonists

The synthesis and structure−activity relationship (SAR) studies of a series of 4‘-oxazolyl-N-(3,4-dimethyl-5-isoxazolyl)[1,1‘-biphenyl]-2-sulfonamide derivatives as endothelin-A (ETA) receptor antagonists are described. The data reveal a remarkable improvement in potency and metabolic stability when the 4‘-position of the biphenylsulfonamide is substituted with an oxazole ring. Additional 2‘-substitution of an acylaminomethyl group further increased the binding activity and provided one of the first subnanomolar ETA-selective antagonists in the biphenylsulfonamide series (17, ETA K i = 0.2 nM). Among the compounds described, 3 (N-(3,4-dimethyl-5-isoxazolyl)-4‘-(2-oxazolyl)[1,1‘-biphenyl]-2-sulfonamide; BMS-193884) had the optimum pharmacological profile and was therefore selected as a clinical candidate for studies in congestive heart failure.