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Discovery of novel protease activated receptors 1 antagonists with potent antithrombotic activity in vivo.

Abstract：

: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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Perez M,Lamothe M,Maraval C,Mirabel E,Loubat C,Planty B,Horn C,Michaux J,Marrot S,Letienne R,Pignier C,Bocquet A,Nadal-Wollbold F,Cussac D,de Vries L,Le Grand B

doi

10.1021/jm900553j

subject

Has Abstract

pub_date

2009-10-08 00:00:00

pages

5826-36

issue

19

eissn

0022-2623

issn

1520-4804

journal_volume

52

pub_type

杂志文章

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