Synthesis and Structure−Activity Relationships of 2-Substituted d-Tryptophan-Containing Peptidic Endothelin Receptor Antagonists:  Importance of the C-2 Substituent of the d-Tryptophan Residue for Endothelin A and B Receptor Subtype Selectivity

Continuing studies on modifications of potent cyclic pentapeptide endothelin (ET) receptor antagonists, represented by BQ-123, and potent linear tripeptide derivative ET receptor antagonists, represented by BQ-788, are described herein. The introduction of d-tryptophan analogues with C-2 substituents in these peptidic ET antagonists resulted in potent ET receptor antagonists with various ETA/ETB subtype selectivity. Combined ETA/ETB receptor antagonists were found in both cyclic pentapeptide and linear tripeptide series with 2-halo- and 2-methyl-d-tryptophans. In contrast, compounds with 2-cyano-d-tryptophan were ETB receptor-selective antagonists. The C-2 substituent of the d-tryptophanyl residue appeared to be very important for the discrimination of ETA/ETB subtype selectivity of the antagonists. The potent ET receptor antagonists with various ETA/ETB subtype selectivity synthesized in this study may be useful tools for elucidating the physiological and pathophysiological roles of ET and ET receptors.