1996
DOI: 10.1021/jm9600914
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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

Abstract: 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 tripept… Show more

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Cited by 21 publications
(16 citation statements)
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“…2-Methyltryptophan is an intermediate in the biosynthesis of the antibiotic thiostrepton, 8 and oligopeptides containing this privileged motif are endothelin receptor antagonists. 19 However, its synthesis is difficult, and often resorts to the union of 2-methylindole with a protected aziridine 19 or an α-aminoenoate. 20 Sigma-Aldrich has now commercialized l - 38c and d - 38c using this chemistry.…”
mentioning
confidence: 99%
See 1 more Smart Citation
“…2-Methyltryptophan is an intermediate in the biosynthesis of the antibiotic thiostrepton, 8 and oligopeptides containing this privileged motif are endothelin receptor antagonists. 19 However, its synthesis is difficult, and often resorts to the union of 2-methylindole with a protected aziridine 19 or an α-aminoenoate. 20 Sigma-Aldrich has now commercialized l - 38c and d - 38c using this chemistry.…”
mentioning
confidence: 99%
“…20 Sigma-Aldrich has now commercialized l - 38c and d - 38c using this chemistry. As for the methylation of a selective ET A endothelin receptor antagonist, BQ-123 ( 39a ), 19,21 selective methylation at the tryptophan C2 position would otherwise require a de novo synthesis starting with 2-methyltryptophan.…”
mentioning
confidence: 99%
“…Fukami et al [47] further studied the SAR of 2-substituted D-Tryptophanyl residues in both linear tripeptide derivatives and cyclic pentapeptide ET antagonists for the discrimination of ET A /ET B receptor subtype selectivity. The synthesis of the tripeptide derivatives and the cyclic pentapeptides with 2-substituted D-tryptophans involved the synthesis of D-tryptophan analogues with C-2 substituents and their subsequent derivatisation.…”
Section: Reagents: A) (Fmoc-leu-) 2 O and Dmap/dmf; B) 20% Piperidinementioning
confidence: 99%
“…Detailed SAR of this class of compounds was also investigated. It was noted that 2-halo and 2-methyl substituents on D-Trp produced combined ET A /ET B antagonists, while compounds with 2-cyano substitution were ET B receptor selective [45]. From these studies an interesting new paradigm evolved in which the Trp was neither in L-configuration nor did it necessarily occupy the carboxy end of the compounds.…”
Section: Et and Et Antagonistsmentioning
confidence: 99%