Discovery of Ro 48-5695: A potent mixed endothelin receptor antagonist optimized from bosentan

Neidhart, Werner; Breu, Volker; Burri, K.; Clozel, Martine; Hirth, Georges; Klinkhammer, Uwe; Giller, Thomas; Ramuz, Henri

doi:10.1016/s0960-894x(97)00400-9

Cited by 35 publications

(18 citation statements)

References 11 publications

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“…RO 48-5695 is a potent, orally available nonpeptide endothelin receptor antagonist that is a derivative of bosentan. 18 RO 48-5695 has a balanced affinity for both the ET-A and ET-B receptors (IC 50 ET-A receptorϭ0.7 nmol/L and IC 50 ET-B receptorϭ5 nmol/L). The dosage of RO 48-5695 was determined on the basis of preliminary studies by Hoffmann-La Roche.…”

Section: Animalsmentioning

confidence: 99%

Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia

et al. 1999

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Background-Endothelin-1 (ET-1) is an endothelium-derived peptide that constricts coronary vessels through stimulation of the ET-A and ET-B receptors. Experimental porcine hypercholesterolemia is associated with impaired coronary endothelial function and elevated ET-1 concentrations. This study was designed to test the hypothesis that chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. Methods and Results-Acetylcholine (10 Ϫ6 to 10 Ϫ4 mol/L) was serially infused into the left anterior descending coronary artery in pigs at baseline and after 12 weeks of a high-cholesterol diet. In the interim, the animals were randomized to 3 groups: Group 1 received no therapy, group 2 received 3 mg/kg per day RO 48-5695, a combined ET-A/ET-B receptor antagonist, and group 3 received 4 mg/kg per day ABT-627, a selective ET-A receptor antagonist. Percent change in coronary artery diameter, coronary blood flow, and coronary vascular resistance were calculated on the basis of quantitative coronary angiography and intracoronary Doppler. At 12 weeks, total cholesterol was significantly and similarly increased in all groups. Chronic endothelin receptor antagonism significantly increased coronary blood flow in response to acetylcholine at 12 weeks (group 1: Ϫ41.6%Ϯ10.7%, group 2: Ϫ4.7%Ϯ11.9%, group 3: 11.4%Ϯ7.4%). Conclusions-Chronic

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Section: Animalsmentioning

confidence: 99%

Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia

et al. 1999

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“…Group 2 animals were placed on oral RO-48-5695 (Hoffmann-La Roche Ltd, Basel, Switzerland), a combined ET-A and ET-B receptor antagonist, on a weight-adjusted scale every 3 weeks to maintain the dose at 3 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 . 20 The dosage of RO-48-5695 was determined on the basis of preliminary studies by Hoffmann-La Roche. Group 3 animals (nϭ8) were placed on ABT-627 (Abbott Laboratories, Abbott Park, Ill) on a weight-adjusted scale to maintain a dose of 4 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 .…”

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confidence: 99%

Coronary Endothelial Function Is Preserved With Chronic Endothelin Receptor Antagonism in Experimental Hypercholesterolemia In Vitro

Best

Lerman

Romero

et al. 1999

ATVB

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Abstract-Hypercholesterolemia is associated with increased circulating and tissue endothelin-1 immunoreactivity, decreased nitric oxide (NO) activity, and altered endothelial function. We tested the hypothesis that chronic endothelin receptor antagonism preserves endothelial function and increases NO in experimental porcine hypercholesterolemia. Pigs were randomized to 3 groups: Group 1, a 2% high-cholesterol (HC) diet alone (nϭ7); group 2, RO-48-5695, a combined endothelin receptor antagonist, and an HC diet (nϭ8); and group 3, ABT-627, a selective endothelin-A receptor antagonist, and an HC diet (nϭ8). Coronary epicardial and arteriolar endothelial function was determined by a dose-response relaxation to bradykinin (10 Ϫ11 to 10 Ϫ6 mol/L), in all groups and in pigs maintained on a normal diet. Plasma total oxidized products of NO (NO x ) were determined by chemiluminescence at baseline and after 12 weeks. Bradykinin-stimulated coronary epicardial and arteriolar relaxation in group 1 was attenuated compared with normal-diet controls. This relaxation was normalized with endothelin receptor antagonism. Plasma NO x decreased after 12 weeks in group 1 (Ϫ74.8Ϯ5.5%). This decrease was attenuated in the endothelin receptor antagonist groups (group 2, Ϫ28.2Ϯ15.0%; group 3, Ϫ38.9Ϯ20.6%). Chronic endothelin receptor antagonism preserves coronary endothelial function and increases NO in hypercholesterolemia. This study supports a role of endothelin-1 in the regulation of NO activity and suggests a possible therapeutic role for endothelin receptor antagonists in hypercholesterolemia.

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“…There are many examples in the literature of biologically active compounds in which a pyrimidine fragment is C-C bonded with a piperidine residue [5][6][7], in fact with 3-and 4-piperidinecarboxylic acid residues.…”

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confidence: 99%

Synthesis of novel 5-piperidyl-substituted 7-hydroxy-3H-1,2,3-triazolo[4,5-d]pyrimidines

Kuleshov

Borovkov

Rodin

et al. 2006

Chem Heterocycl Compd

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Discovery of Ro 48-5695: A potent mixed endothelin receptor antagonist optimized from bosentan

Cited by 35 publications

References 11 publications

Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia

Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia

Coronary Endothelial Function Is Preserved With Chronic Endothelin Receptor Antagonism in Experimental Hypercholesterolemia In Vitro

Synthesis of novel 5-piperidyl-substituted 7-hydroxy-3H-1,2,3-triazolo[4,5-d]pyrimidines

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