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

Fukami, Tatsuki; Yamakawa, Takeru; Kojima, Hisaki; Amano, Yuka; Ihara, Masaki; Yano, Mitsuo; Ishikawa, Kiyofumi

doi:10.1016/0960-894x(95)00237-n

Cited by 4 publications

(6 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The synthesis of the tripeptide derivatives and the cyclic pentapeptides with 2-substituted d -tryptophans described in this article involves the synthesis of d -tryptophan analogues with C-2 substituents and their subsequent derivation. The d -tryptophan analogues with 2-halo, 2-cyano, and 2-ethynyl substituents were synthesized according to the method given in our previous paper (Scheme ) . The protected 2-halo- d -tryptophans 54a , b were synthesized by radical halogenation of the protected d -tryptophan 53 according to the method reported by Phillips and Cohen …”

Section: Chemistrymentioning

confidence: 99%

“…Of the derivatives comprising d -tryptophan analogues with modifications on the indole ring, potent ET A /ET B -nonselective and ET B -selective receptor antagonists were found in 2-substituted d -tryptophan-containing tripeptide derivatives. For example, the 2-bromo- d -tryptophan-containing linear tripeptide derivative BQ-928 ( 4 ) is a combined ET A /ET B receptor antagonist, while the 2-cyano- d -tryptophan-containing derivative BQ-017 ( 5 ) is an ET B -selective antagonist . Since then, we introduced the 2-substituted d -tryptophan analogues into the head-to-tail cyclic pentapeptides that are represented by 1 and found some potent ET receptor antagonists with various ET A /ET B receptor subtype selectivity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 1996

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 1996

Self Cite

View full text Add to dashboard Cite

show abstract

“…For that purpose, we have used a highly potent mixed ET A /ET B receptor antagonist, SB 209670 (Ohlstein et al , 1994), together with BQ‐123 and another selective ET A receptor antagonist, BMS 182874 (Stein et al , 1994). In addition, a recent study by Fukami et al (1995, 1996) disclosed two new mixed ET A /ET B receptor antagonists, namely BQ‐928 and BQ‐238. These antagonists have, as interesting characteristics, inverse affinities for the two receptor populations.…”

Section: Introductionmentioning

confidence: 99%

Pharmacology of two novel mixed ET_A/ET_B receptor antagonists, BQ‐928 and 238, in the carotid and pulmonary arteries and the perfused kidney of the rabbit

Maurice

Gratton

D’Orléans-Juste

1997

British J Pharmacology

View full text Add to dashboard Cite

1 In the present study, we have pharmacologically characterized two novel mixed endothelin ET A /ET B receptor antagonists, namely BQ-928 and BQ-238, in ET A and ET B preparations, the rabbit carotid artery (RbCA) and the rabbit pulmonary artery (RbPA), respectively. These two antagonists were compared to established ET A (BQ-123 and BMS 182874), ET B (BQ-788) and mixed ET A /ET B (SB 209670) receptor antagonists. 2 In the RbCA, the ET A monoreceptor preparation, BQ-238 and BQ-928 had apparent a nities (pA 2 ) of 7.42+0.22 and 7.22+0.18, respectively, BQ-788 being inactive in this preparation. In the ET B monoreceptor preparation, the RbPA (when IRL-1620 was used as an ET B receptor agonist), the pA 2 for BQ-238 was 7.05+0.14 and for BQ-928 was 8.43+0.04. BQ-123 and BMS 182874 were inactive in this preparation. Similar to SB 209670, BQ-238 but not BQ-928 had a higher a nity for the ET A than the ET B receptor. 3 All of the antagonists were tested for their ability to block and reverse endothelin-1-induced vasoconstrictions in the rabbit perfused kidney. In this preparation endothelin-1-induced increases in vascular resistance have been shown to be mediated solely by ET A receptors. All compounds (except BQ-788) blocked the pressor e ects of endothelin within the kidney; the calculated IC 50 values for BQ-123, BMS 182874, SB 209670, BQ-928 and BQ-238 were 0.4 mM, 2 mM, 0.01 mM, 0.4 mM and 0.09 mM, respectively. 4 In all experiments in the rabbit perfused kidney, endothelin-1 was readministered for a third time, 60 min following cessation of infusion of the above-mentioned antagonists. The response to the third infusion of endothelin-1 following cessation of infusion of BQ-123, BMS 182874 and SB 209670 was not signi®cantly di erent from that to the third infusion of endothelin in control conditions. However, the response to endothelin-1 was signi®cantly higher than control in tissues pre-infused with BQ-788 or BQ-928 (56+9 and 41.6+15%, respectively, n=8 each, P50.05). 5 Our results suggest that in a system where ET A receptor activation is responsible for vasoconstriction and ET B -receptor activation for vasodilatation, ET A receptor selective antagonists or mixed ET A /ET B receptor antagonists which possess high a nity for ET A receptors do not induce hyperresponsiveness to endothelin-1. In contrast, ET B selective antagonists or mixed antagonists possessing a high a nity for ET B receptors (such as BQ-928) interfere with the ET B -receptor-dependent physiological antagonism of endothelin-1-induced pressor responses in these same tissues.

show abstract

“…The 2-methyl Dtryptophan analogues (23 and 24) were prepared by Sato and Kozikowski [48], as shown in scheme 4. The introduction of 2-halo and 2-methyl-D-tryptophans produced combined ET A /ET B receptor antagonists while the introduction of 2-cyano-D-tryptophan afforded ET B antagonists decreasing 5)) is a combined ET A /ET B receptor antagonist while the 2-cyano-D-tryptophan containing derivative BQ-017 (19) is an ET B selective antagonist [49].…”

Section: Reagents: A) (Fmoc-leu-) 2 O and Dmap/dmf; B) 20% Piperidinementioning

confidence: 99%

“…One of the most important sulfonamide antagonists is the acylsulfonamide L-749329 (49) [93] (Fig. (12)).…”

Section: Recently Murugesan and Co-workers (Bristol-myersmentioning

confidence: 99%

Endothelin Receptor Antagonists: An Overview of Their Synthesis and Structure-Activity Relationship

Iqbal¹,

Sanghi²,

Das

2005

MRMC

View full text Add to dashboard Cite

Endothelins (ETs) are potent vasoconstrictor peptides and are associated with several disease states like pulmonary hypertension, systemic hypertension and heart failure. Endothelin-1 (ET-1) is the first member of the family and it has the receptor subtypes known as ETA and ETB. The receptors ETA and ETB are attractive new therapeutic targets for diseases associated with elevated ET-1 levels. Several studies have thus led to the discovery of selective ETA receptor antagonists as well as non-selective ETA/ETB antagonists. The preclinical and clinical studies have clearly established that these antagonists are effective in the treatment of essential hypertension, pulmonary hypertension, heart failure and atherosclerosis. The advances in this area have resulted in the FDA approval of the orally active dual antagonist Bosentan for pulmonary hypertension in 2001. This review highlights the synthesis and structure-activity of the endothelin receptor antagonists and covers the literature in this area up to 2001.

show abstract

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

Cited by 4 publications

References 16 publications

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

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

Pharmacology of two novel mixed ET_A/ET_B receptor antagonists, BQ‐928 and 238, in the carotid and pulmonary arteries and the perfused kidney of the rabbit

Endothelin Receptor Antagonists: An Overview of Their Synthesis and Structure-Activity Relationship

Contact Info

Product

Resources

About

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

Cited by 4 publications

References 16 publications

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

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

Pharmacology of two novel mixed ETA/ETB receptor antagonists, BQ‐928 and 238, in the carotid and pulmonary arteries and the perfused kidney of the rabbit

Endothelin Receptor Antagonists: An Overview of Their Synthesis and Structure-Activity Relationship

Contact Info

Product

Resources

About

Pharmacology of two novel mixed ET_A/ET_B receptor antagonists, BQ‐928 and 238, in the carotid and pulmonary arteries and the perfused kidney of the rabbit