Discovery of Novel Protease Activated Receptors 1 Antagonists with Potent Antithrombotic Activity in Vivo

Protease activated receptors (PARs) or thrombin receptors constitute a class of G-protein-coupled receptors (GPCRs) implicated in the activation of many physiological mechanisms. Thus, thrombin activates many cell types such as vascular smooth muscle cells, leukocytes, endothelial cells, and platele...

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Published in:Journal of medicinal chemistry 2009-10, Vol.52 (19), p.5826-5836
Main Authors: Perez, Michel, Lamothe, Marie, Maraval, Catherine, Mirabel, Etienne, Loubat, Chantal, Planty, Bruno, Horn, Clemens, Michaux, Julien, Marrot, Sebastien, Letienne, Robert, Pignier, Christophe, Bocquet, Arnaud, Nadal-Wollbold, Florence, Cussac, Didier, de Vries, Luc, Le Grand, Bruno
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Drug Discovery
Drug-Related Side Effects and Adverse Reactions
Fibrinolytic Agents - administration & dosage
Fibrinolytic Agents - chemical synthesis
Humans
Medical sciences
Pharmacology. Drug treatments
Piperazines - pharmacology
Platelet Aggregation Inhibitors - administration & dosage
Platelet Aggregation Inhibitors - chemical synthesis
Platelet Aggregation Inhibitors - pharmacology
Pyridines - pharmacology
Rats
Receptor, PAR-1 - antagonists & inhibitors
Structure-Activity Relationship
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Summary:Protease activated receptors (PARs) or thrombin receptors constitute a class of G-protein-coupled receptors (GPCRs) implicated in the activation of many physiological mechanisms. Thus, thrombin activates many cell types such as vascular smooth muscle cells, leukocytes, endothelial cells, and platelets via activation of these receptors. In humans, thrombin-induced platelet aggregation is mediated by one subtype of these receptors, termed PAR1. This article describes the discovery of new antagonists of these receptors and more specifically two compounds: 2-[5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)penta-1,3-dienyl]benzonitrile 36 (F 16618) and 3-(2-chlorophenyl)-1-[4-(4-fluorobenzyl)piperazin-1-yl]propenone 39 (F 16357), obtained after optimization. Both compounds are able to inhibit SFLLR-induced human platelet aggregation and display antithrombotic activity in an arteriovenous shunt model in the rat after iv or oral administration. Furthermore, these compounds are devoid of bleeding side effects often observed with other types of antiplatelet drugs, which constitutes a promising advantage for this new class of antithrombotic agents.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm900553j