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 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.
Perez
Michel
M
Medicinal Chemistry 4 Division, Pierre Fabre Research Center, Castres Cedex, France. michel.perez@pierre-fabre.com
Lamothe
Marie
M
Maraval
Catherine
C
Mirabel
Etienne
E
Loubat
Chantal
C
Planty
Bruno
B
Horn
Clemens
C
Michaux
Julien
J
Marrot
Sebastien
S
Letienne
Robert
R
Pignier
Christophe
C
Bocquet
Arnaud
A
Nadal-Wollbold
Florence
F
Cussac
Didier
D
de Vries
Luc
L
Le Grand
Bruno
B
D000818:Animals; D055808:Drug Discovery; D064420:Drug-Related Side Effects and Adverse Reactions; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000138:chemical synthesis*; D006801:Humans; D010879:Piperazines / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
C542252:2-(5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)penta-1,3-dienyl)benzonitrile; D005343:Fibrinolytic Agents; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines