RESUMO
High-throughput screening resulted in the identification of a small molecule inhibitor of PAR1. Optimisation of the initial hit led to the discovery of compounds 34 and 49, which displayed antithrombotic activity in an arteriovenous shunt model in the rat after iv administration.
Assuntos
Descoberta de Drogas/métodos , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Receptor PAR-1/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/fisiologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Ratos , Receptor PAR-1/fisiologia , Relação Estrutura-AtividadeRESUMO
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.