The discovery and structure - Activity relationships of nonpeptide, low molecular weight antagonists selective for the endothelin ET(B) receptor

Article abstract of DOI:10.1016/S0968-0896(98)80010-2

The systematic modification of the ET(A) selective N-(5-isoxazolyl)benzene-sulfonamide endothelin antagonists to give ET(B) 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 ET(B) antagonist. Larger substituents caused a decrease in both ET(B) activity and selectivity. A similar trend was observed by substitution at the 5-position of the N-(5-isoxazolyl)-2-thiophenesulfonamide ET(A) receptor antagonists. The para-tolyl group was again found to be optimal for the ET(B) activity and selectivity. The structural features that were found to be favorable for binding to the ET(B) receptor, that is, the presence of a linear, conjugated π-system of definite shape and size, have been successfully incorporated into the design of ET(B) selective polycyclic aromatic sulfonamides antagonists. Copyright (C) 1998 Elsevier Science Ltd.