Synthesis of 2-substituted d-tryptophan-containing peptide derivatives with endothelin receptor antagonist activity

✍ Scribed by Takehiro Fukami; Takeru Yamakawa; Hisaki Kojima; Yuuka Amano; Masaki Ihara; Mitsuo Yano; Kiyofumi Ishikawa

• Book ID: 103982981
• Publisher: Elsevier Science
• Year: 1995
• Tongue: English
• Weight: 347 KB
• Volume: 5
• Category: Article
• ISSN: 0960-894X
• DOI: 10.1016/0960-894x(95)00237-n

✦ Synopsis

Peptide derivatives with 2-substituted D-tryptophan analogues were synthesized. All prepared peptide derivatives showed potent affinity for ETa receptors, while their ETA affinity depended on the substituents of the D-tryptophanyl residue. A 2-bromo-D-tryptophan derivative 16b (BQ-928) was a combined ETA/ETa receptor antagonist and a 2-cyano-D-tryptophan derivative 17c (BQ-017) was a selective ETa receptor antagonist.

Endothelin (ET)-I, which was first isolated from the culture medium of porcine aortic endothelial cells, is a potent vasoconstrictor consisting of 21 amino acids. 1 Studies including a human genomic analysis have identified two structurally-and functionally-related isopeptides of ET-1 termed ET-2 and ET-3.2,3,4 Several studies have demonstrated that there are at least two different ET receptor subtypes, ETA and ETa. 5,6,7 Since these discoveries, many efforts have been made to identify ET receptor antagonists because they may lead to the development of useful therapeutic agents. 8 We disclosed a selective ETA receptor antagonist, BQ-123, 9 and a selective ETa receptor antagonist, BQ-788.1° In the course of our work on the discovery of BQ-788, one of the