Ethenesulfonamide and ethanesulfonamide derivatives, a novel class of orally active endothelin-A receptor antagonists.

Abstract In the previous paper, we described a series of 2-phenylethenesulfonamide derivatives, a novel class of ET A -selective endothelin (ET) receptor antagonists, including the 2-methoxyethoxy derivative 2a and the 2-fluoroethoxy derivative ( 2b ). In this paper, we wish to report further details of structure–activity relationships (SARs) of the two regions of the molecule in compound 2b , which were the alkoxy region at the 6-position of the core pyrimidine ring and the 2-phenylethenesulfonamide region. In these modifications, replacement of the 2-fluoroethoxy group with a methoxy group ( 6e ) and replacement of the 2-phenylethenesulfonamide group with a 2-(pyridin-3-yl)ethenesulfonamide group ( 6l ) or 2-phenylethanesulfonamide group ( 6q ) were well tolerated both in the ET A binding affinity and ET A selectivity. Among them, compound 6e showed further improvement in oral activity compared to 2b . After oral administration, compound 6e inhibited the big ET-1 induced pressor response in conscious rats at 0.3 mg /kg with a duration of >6.5 h. Compound 6e also exhibited a potent antagonistic activity in the pithed rats.