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

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.

Structure-activity relationships of N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides as selective endothelin receptor-A antagonists.

We report here that N2-aryl-3-(isoxazolylsulfamoyl)-2-thiophenecarboxamides are potent and selective small molecule ETA receptor antagonists. The aryl group was subjected to extensive structural modification. With monosubstitution, the para position was most useful in increasing potency, with methyl being preferred. With disubstitution, 2,4-disubstitution further enhanced activity with methyl or cyano groups being preferred at the 2-position. In this series, a benzo-[d][1,3]dioxole group is equivalent to a 4-methyl group in in vitro activity and afforded the compounds with both in vivo activity and moderate half-lives.

Synthesis and conformational analysis of cyclic pentapeptide endothelin antagonists.

Two endothelin antagonists cyclo(D-Leu-D-Val-Pro-D-Asp-Trp) (IPI-147), and cyclo (D-Trp-D-Asp-Ac3c-D-Val-Leu) (IPI-725) have been synthetized. Their solution conformations have been studied in aqueous solution by NMR spectroscopy and dynamics simulation. Activity studies show that IPI-725 is a strong ETA antagonist, while IPI-147 is a weak ETA antagonist. Comparison of the solution conformations of these two ETA antagonists suggests that the difference in their activities results from their structural differences. IPI-147 contains a type II beta-turn with a hydrogen bond between NH of D-Val and the C = O of D-Asp. IPI-725, on the other hand, contains two turns, a type II beta-turn with a hydrogen bond between NH of D-Asp and C = O of D-Val, as well as a gamma'-turn with a hydrogen bond formed between D-Val NH and D-Asp carbonyl group. Therefore IPI-147 appears to be more flexible than IPI-725. Although both beta-turns contain the same residues, their orders in the turn are reversed. The beta-turn in IPI-725 is formed with D-Val:Leu:D-Trp:D-Asp, while in IPI-147, the beta-turn is formed with D-Asp:Trp:D-Leu:D-Val. The activities and solution conformations of IPI-147 and IPI-725 were also compared with BQ-123 [cyclo(D-Trp-D-Asp-Pro-D-Val-Leu)], a well characterized, highly potent endothelin antagonist.