Synthesis and Structure—Activity Relationships in a Series of Ethenesulfonamide Derivatives, a Novel Class of Endothelin Receptor Antagonists

Abstract

In the previous paper, we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ET_A-selective endothelin (ET) receptor antagonists, including the compounds 1a, b. Compound 1a showed excellent oral antagonistic activities and pharmacokinetic profiles, and the monopotassium salt of 1 (YM-598 monopotassium) is in clinical trials. In this paper, we wish to report the investigation of the further details of structure-activity relationships (SARs) of the 2-phenylethenesulfonamide region in 1a. It was found that methyl substitutions at the 2-, 4- and 6-positions of the phenyl group in 1a led to the discovery of the ET_A/ET_B mixed antagonist (6s) with an IC₅₀ of 2.2nM for the ET_A receptor. We also found that introduction of an ethyl group to the 1-position of the ethenyl group in 1a gave the ET_A selective antagonist (6u) with an oral endothelin antagonistic activity in rats.