Synthesis and structure-activity relationships of potent and orally activesulfonamide ETB selective antagonists

The synthesis and structure-activity relationships of a series of N-pyrimid inyl benzenesulfonamides as ETB selective antagonists are described. N-Isox azolyl benzenesulfonamide 1a. previously reported,(1) was selected as a lea d compound, and isosteric replacement of the isoxazole ring of la with a py rimidine ring led to the discovery of the highly potent ETB selective antag onist 6e with oral bioavailability. Modification of the terminal aldehyde g roup at the 6-position of the pyrimidine ring was investigated, and malonat e 15b and acylhydrazone 16f were found to be equipotent to aldehyde 6e. Com pound 6e showed ETB antagonistic activity on in vivo evaluation. (C) 2001 E lsevier Science Ltd. All rights reserved.