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

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• 作者：Michel Perez ; Marie Lamothe ; Catherine Maraval ; Etienne Mirabel ; Chantal Loubat ; Bruno Planty ; Clemens Horn ; Julien Michaux ; Sebastien Marrot ; Robert Letienne ; Christophe Pignier ; Arnaud Bocquet ; Flor
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：October 8, 2009
• 年：2009
• 卷：52
• 期：19
• 页码：5826-5836
• 全文大小：901K
• 年卷期：v.52,no.19(October 8, 2009)
• ISSN：1520-4804

文摘

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.