The systematic modification of the ETA selective N-(5-isoxazolyl)benzene-sulfonamide endothelin antagonists to give ETB selective antagonists is reported. The reversal in selectivity was brought about by substitution of the 4-position with aryl and substituted aryl groups. Of all the aromatic substituents studied, the para-tolyl group gave rise to the most active and selective ETB antagonist. Larger substituents caused a decrease in both ETB activity and selectivity. A similar trend was observed by substitution at the 5-position of the N-(5-isoxazolyl)-2-thiophenesulfonamide ETA receptor antagonists. The para-tolyl group was again found to be optimal for the ETB activity and selectivity. The structural features that were found to be favorable for binding to the ETB receptor, that is, the presence of a linear, conjugated pi-system of definite shape and size, have been successfully incorporated into the design of ETB selective polycyclic aromatic sulfonamides antagonists.