The chemical syntheses and bioactivities of novel peptide‐based endothelin antagonists

Endothelin antagonists, novel tripeptides containing a series of unnatural amino acids, were synthesized and characterized. A linear peptide BQ-485, perhydroazepin-1-yl-L-leucyl (1)-D-tryptophanyl (2)-D-tryptophan (3), was selected as the parent compound. The introduction of D-Phe derivatives into these peptidic ET antagonists resulted in potent activity against the contraction of rat aortic smooth muscles induced by ET-1 (10 nM) which activated the ET receptors. Among these compounds, 15 tripeptides had high enough antagonistic activity at the level of 10(-7) mol/L (IC50). The activity of three compounds was 10(-6) mol/L (IC50). These HIM-CO-Leu-D-Trp-D-Phe(-R)-OH compounds as ETA antagonists may provide a tool for the development of therapeutic agents in the treatment of putative ET-1-related disorders.