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4 results on '"Volker Breu"'

1. The Discovery of Nonpeptide Endothelin Receptor Antagonists. Progression towards Bosentan

Author

Werner Neidhart, Volker Breu, Daniel Bur, Kaspar Burri, Martine Clozel, Georges Hirth, Marcel Müller, Hans P. Wessel, and Henri Ramuz

Subjects
Chemistry, QD1-999
Abstract

Since its discovery, endothelin-1 has attracted considerable scientific interest for its extremely potent and long-lasting vasoconstrictor effect and its binding to G-protein-coupled receptors. The endothelins appear to be part of a functional regulatory system in the circulation and strong evidence has accumulated for their involvement in clinical disorders associated with vasoconstriction (e.g. renal failure, congestive heart failure).In a program aimed at identifying nonpeptide ET receptor antagonists, a distinct class of substituted arylsulfonamido pyrimidines was discovered from a chemical substance library. Lead optimization led to orally active antagonists of ETA and ETB receptors possessing mixed or receptor-subtype-selective profiles in the low nanomolar range. From these compounds, the mixed antagonist bosentan was selected for development; it shows efficacy in several pathophysiological models of local and systemic vasoconstriction and promising clinical results in patients suffering from congestive heart failure.Chemical modifications in this structural class in combination with X-ray crystal data analysis for key compounds led to more in-depth understanding of antagonist-receptor interaction. Structural determinants of bosentan binding to the ETA receptor were defined on the molecular level by site-directed mutagenesis experiments. This led to a 3D model of the antagonist binding domain which proved valuable to rationalize structure-activity relationships.

Published
1996

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

Author

Werner Neidhart, Martine Clozel, Volker Breu, Georges Hirth, Henri Ramuz, and Kaspar Burri

Subjects
Endothelin Receptor Antagonists, Endothelin receptor type A, Non peptide antagonist, Receptors, Peptide, Biophysics, CHO Cells, Viper Venoms, Pharmacology, In Vitro Techniques, Endothelin ETA receptor, Biochemistry, Binding, Competitive, Endothelin, Endothelin antagonist, Structural Biology, Cricetinae, Microsomes, Genetics, Animals, Humans, Vasoconstrictor Agents, Molecular Biology, Etb receptor, Sulfonamides, Arachidonic Acid, Molecular Structure, Chemistry, Receptors, Endothelin, Rightward shift, Cell Membrane, Antagonist, Cell Biology, respiratory system, musculoskeletal system, Endothelin 1, Receptor, Endothelin B, In vitro, Recombinant Proteins, Rats, Pyrimidines, Vasoconstriction, cardiovascular system, Endothelin receptor, Endothelin ETB receptor, Muscle Contraction, Protein Binding, circulatory and respiratory physiology
Abstract

We describe here Ro 46-8443, the first non-peptide endothelin ETB receptor selective antagonist. It displays up to 2000-fold selectivity for ETB receptors both in terms of binding inhibitory potency and functional inhibition. The observed parallel rightward shift of concentration-response curves with different antagonist concentrations is consistent with a competitive binding mode. Since Ro 46-8443 selectively inhibits ETB receptor mediated responses, it is a valuable tool for clarifying the role of ETB receptors in pathology.

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3. In vitro characterization of Ro 46-2005, a novel synthetic non-peptide endothelin antagonist of ETA and ETB receptors

Author

Bernd-Michael Löffler, Volker Breu, and Martine Clozel

Subjects
Endothelin Receptor Antagonists, Swine, Placenta, Moths, Biochemistry, Muscle, Smooth, Vascular, chemistry.chemical_compound, Non-competitive inhibition, Structural Biology, Pregnancy, Cerebellum, Receptor, Aorta, Cells, Cultured, Sulfonamides, Arachidonic Acid, Receptors, Endothelin, Endothelins, Endothelin receptor, Receptor antagonist, Recombinant Proteins, Glomerular Mesangium, Arachidonic acid, Female, Endothelin: Endothelin antagonist, medicine.medical_specialty, Endothelin receptor type A, medicine.drug_class, Biophysics, Transfection, Binding, Competitive, Cell Line, Internal medicine, Microsomes, Genetics, medicine, Animals, Humans, Molecular Biology, IC50, Antagonist, Muscle, Smooth, Cell Biology, Intracellular Membranes, Molecular biology, Rats, Arachidonic acid release, Kinetics, Endocrinology, Pyrimidines, chemistry
Abstract

Ro 46-2005 is a new synthetic non-peptide endothelin (ET) receptor antagonist. In binding experiments, Ro 46-2005 proved to be equipotent (IC50 200–500 nM) for inhibition of [125I]ET-1 binding on the two known ET receptor subtypes (ETA and ETB). Scatchard analysis was consistent with a competitive binding mode. Ro 46-2005 also inhibited the functional consequences of ET-1 stimulation: the ET-1-induced release of arachidonic acid from rat mesangial cells was inhibited with an IC50 of 1.8 μM.

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

Author

Volker Breu and Martine Clozel

Subjects
Endothelin Receptor Antagonists, medicine.medical_specialty, Endothelin receptor antagonist, Arginine, Biophysics, Blood Pressure, Viper Venoms, Biochemistry, Peptides, Cyclic, Rats, Inbred WKY, Endothelin, Nitric oxide, chemistry.chemical_compound, Structural Biology, Internal medicine, Rats, Inbred SHR, Genetics, medicine, Animals, ETB receptor, Molecular Biology, Hypertensive rat, Sulfonamides, biology, Receptors, Endothelin, Antagonist, Cell Biology, respiratory system, musculoskeletal system, Receptor, Endothelin B, Blockade, Rats, Nitric oxide synthase, Endocrinology, Blood pressure, NG-Nitroarginine Methyl Ester, Pyrimidines, chemistry, Hypertension, biology.protein, cardiovascular system, Nitric Oxide Synthase, Endothelin receptor, circulatory and respiratory physiology
Abstract

We used Ro 46-8443, non-peptidic antagonist selective of endothelin ETB receptors, to study the role of ETB 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 ETB-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’ ETB receptors, while in normotensive rats the prevailing role of ETB receptors seems to be in mediating a vasoconstrictor tone.

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