title: The chemical syntheses and bioactivities of novel peptide-based endothelin antagonists.
abstract: 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.
authors: Department of Chemistry, Tsinghua University, Beijing, China.
authors: W
authors: W
authors: Yu
authors: Y
authors: Y
authors: Liang
authors: K
authors: K
authors: Liu
authors: Y
authors: Y
authors: Zhao
authors: G
authors: G
authors: Fei
authors: H
authors: H
authors: Wang
mesh_terms: D000818:Animals; D001011:Aorta; D001381:Azepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D013329:Structure-Activity Relationship; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors* / Q000494:pharmacology
chemical_list: D001381:Azepines; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010455:Peptides; D044022:Receptor, Endothelin A; D014662:Vasoconstrictor Agents; C083116:BQ 485