Synthesis and structure-activity relationships in a series of ethenesulfonamide derivatives, a novel class of endothelin receptor antagonists

In the previous paper, we described a series of the 2-arylethenesulfonamide derivatives, a novel class of ETA-selective endothelin (ET) receptor antag onists, including the compounds 1a, b. Compound la showed excellent oral an tagonistic activities and pharmacokinetic profiles, and the monopotassium s alt of 1 (YM-598 monopotassium) is in clinical trials. In this paper, we wi sh 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 pheny l group in 1a led to the discovery of the ETA/ETB mixed antagonist (6s) wit h an IC50 of 2.2 nm for the ETA receptor. We also found that introduction o f an ethyl group to the 1-position of the ethenyl group in la gave the ETA selective antagonist (6u) with an oral endothelin antagonistic activity in rats.