The discovery and structure-activity relationships of nonpeptide, low molecular weight antagonists selective for the endothelin ETB receptor

The systematic modification of the ETA selective N-(5-isoxazolyl)benzene-su lfonamide endothelin antagonists to give ETB selective antagonists is repor ted. The reversal in selectivity was brought about by substitution of the 4 -position with aryl and substituted aryl groups. Of all the aromatic substi tuents studied, the para-tolyl group gave rise to the most active and selec tive ETB antagonist. Larger substituents caused a decrease in both ETB acti vity and selectivity. A similar trend was observed by substitution at the 5 -position of the N-(5-isoxazolyl)-2-thiophenesulfonamide ETA receptor antag onists. The para-tolyl group was again found to be optimal for the ETB acti vity and selectivity. The structural features that were found to be favorab le for binding to the ETB receptor, that is, the presence of a linear, conj ugated pi-system of definite shape and size, have been successfully incorpo rated into the design of ETB selective polycyclic aromatic sulfonamides ant agonists. (C) 1998 Elsevier Science Ltd. All rights reserved.