In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET<sub>B</sub> receptor

Breu, Volker; Clozel, Martine; Burri, K.; Hirth, Georges; Neidhart, Werner; Ramuz, Henri

doi:10.1016/0014-5793(96)00213-x

Cited by 44 publications

(13 citation statements)

References 31 publications

(34 reference statements)

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“…We have shown in a separate manuscript [8] that Ro 46-8443 is a selective antagonist of the ETB receptor and inhibits in vitro various responses mediated by this receptor. No partial agonistic effect was detected.…”

Section: Discussionmentioning

confidence: 87%

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The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443

Clozel

Breu

1996

FEBS Letters

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We used Ro 46-8443, non-peptidic antagonist selective of endothelin ETB receptors, to study the role of ET8 receptors in rat hypertension models. In normotensive rats, Ro 46-8443 decreased blood pressure, but in SHR and DOCA rats, it induced a pressor effect, due to blockade of ETs-mediated release of nitric oxide since L-NAME prevented it. In rats rendered hypertensive by chronic L-NAME, Ro 46-8443 did not induce a pressor but depressor effect. Thus, in DOCA rats and SHR, Ro 46-8443 reveals a predominant influence of endothelial 'vasorelaxant' ETa receptors, while in normotensive rats the prevailing role of ETn receptors seems to be in mediating a vasoconstrictor tone.

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Section: Discussionmentioning

confidence: 87%

“…We have already described Ro 46-2005 and bosentan (Ro 47-0203) as the first synthetic non-peptide mixed antagonists of ET receptors [6,7]. We are now describing [8] …”

Section: Introductionmentioning

confidence: 99%

The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443

Clozel

Breu

1996

FEBS Letters

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“…Our modeling suggests that a 10‐fold selective ET B vs ET A antagonist might be ideal in antagonizing the pulmonary artery ET B receptors in the presence of CLEARANCE (Figure B). Ro 46‐8443 is 25‐fold selective for ET B vs ET A , and modeling would suggest that with a p K B of 7.1 at ET B receptors (Figure D), a plasma level would be required of nearly 10 μmol L −1 to give a 10‐fold antagonism of ET B receptors, but ET A antagonism would not be sufficient if inhibition of clearance presented a higher level of endothelin‐1. Another nonselective and potent ET A and ET B antagonist with selectivity ratio of just 3, A‐182086 (Table ), has been used in animals and shows that effective ET A and ET B receptor antagonism was achieved after oral dosing …”

Section: Discussionmentioning

confidence: 99%

Distortion of K_B estimates of endothelin‐1 ET_A and ET_B receptor antagonists in pulmonary arteries: Possible role of an endothelin‐1 clearance mechanism

Angus

Hughes

Wright

2017

Pharmacology Res & Perspec

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Dual endothelin ETA and ETB receptor antagonists are approved therapy for pulmonary artery hypertension (PAH). We hypothesized that ETB receptor‐mediated clearance of endothelin‐1 at specific vascular sites may compromise this targeted therapy. Concentration‐response curves (CRC) to endothelin‐1 or the ETB agonist sarafotoxin S6c were constructed, with endothelin receptor antagonists, in various rat and mouse isolated arteries using wire myography or in rat isolated trachea. In rat small mesenteric arteries, bosentan displaced endothelin‐1 CRC competitively indicative of ETA receptor antagonism. In rat small pulmonary arteries, bosentan 10 μmol L−1 left‐shifted the endothelin‐1 CRC, demonstrating potentiation consistent with antagonism of an ETB receptor‐mediated endothelin‐1 clearance mechanism. Removal of endothelium or L‐NAME did not alter the EC 50 or Emax of endothelin‐1 nor increase the antagonism by BQ788. In the presence of BQ788 and L‐NAME, bosentan displayed ETA receptor antagonism. In rat trachea (ETB), bosentan was a competitive ETB antagonist against endothelin‐1 or sarafotoxin S6c. Modeling showed the importance of dual receptor antagonism where the potency ratio of ETA to ETB antagonism is close to unity. In conclusion, the rat pulmonary artery is an example of a special vascular bed where the resistance to antagonism of endothelin‐1 constriction by ET dual antagonists, such as bosentan or the ETB antagonist BQ788, is possibly due to the competition of potentiation of endothelin‐1 by blockade of ETB‐mediated endothelin‐1 clearance located on smooth muscle and antagonism of ETA‐ and ETB‐mediated contraction. This conclusion may have direct application for the efficacy of endothelin‐1 antagonists for treating PAH.

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“…Actelion in Europe and Genentech in the US market it under the trade name Tracleer. Breu et al [69] described in vitro characterization of Ro-46-8443 (28), the first non-peptide antagonist selective for the endothelin ET B receptor. It is a sulfonamide with central pyrimidine moiety and is structurally related to 26 and Bosentan (see Fig.…”

Section: Sulfonamidesmentioning

confidence: 99%

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

Iqbal¹,

Sanghi²,

Das

2005

MRMC

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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.

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In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor

Cited by 44 publications

References 31 publications

The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443

The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443

Distortion of K_B estimates of endothelin‐1 ET_A and ET_B receptor antagonists in pulmonary arteries: Possible role of an endothelin‐1 clearance mechanism

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

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In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ETB receptor

Cited by 44 publications

References 31 publications

The role of ETB receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ETB receptor antagonist Ro 46‐8443

The role of ETB receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ETB receptor antagonist Ro 46‐8443

Distortion of KB estimates of endothelin‐1 ETA and ETB receptor antagonists in pulmonary arteries: Possible role of an endothelin‐1 clearance mechanism

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

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Product

Resources

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In vitro characterisation of Ro 46‐8443, the first non‐peptide antagonist selective for the endothelin ET_B receptor

The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443

The role of ET_B receptors in normotensive and hypertensive rats as revealed by the non‐peptide selective ET_B receptor antagonist Ro 46‐8443

Distortion of K_B estimates of endothelin‐1 ET_A and ET_B receptor antagonists in pulmonary arteries: Possible role of an endothelin‐1 clearance mechanism