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.
Fukami
T
T
Drug Discovery Research Laboratories, Tsukuba Research Institute, Banyu Pharmaceutical Company, Ltd., Ibaraki, Japan.
Yamakawa
T
T
Niiyama
K
K
Kojima
H
H
Amano
Y
Y
Kanda
F
F
Ozaki
S
S
Fukuroda
T
T
Ihara
M
M
Yano
M
M
Ishikawa
K
K
D000818:Animals; D015195:Drug Design; D065128:Endothelin Receptor Antagonists; D006801:Humans; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013552:Swine; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D014665:Vasodilator Agents; C086539:BQ 788; D014364:Tryptophan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)