SAR216471, an alternative to the use of currently available P2Y₁₂ receptor inhibitors?
| Autor: | N, Delesque-Touchard, A M, Pflieger, S, Bonnet-Lignon, L, Millet, V, Salel, C, Boldron, G, Lassalle, J M, Herbert, P, Savi, F, Bono |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Blood Platelets
Male Indoles Platelet Aggregation Administration Oral Biological Availability Hemorrhage CHO Cells Transfection Binding Competitive Rats Sprague-Dawley Cricetulus Fibrinolytic Agents Animals Humans Dose-Response Relationship Drug Receptors Purinergic P2 Thrombosis Thionucleotides Receptors Purinergic P2Y12 Adenosine Diphosphate Pyridazines Disease Models Animal Purinergic P2Y Receptor Antagonists Platelet Aggregation Inhibitors Protein Binding Signal Transduction |
| Zdroj: | Thrombosis research. 134(3) |
| ISSN: | 1879-2472 |
| Popis: | P2Y12 antagonism is a key therapeutic strategy in the management and prevention of arterial thrombosis. The objective of this study was to characterize the pharmacodynamic (PD) and pharmacokinetic (PK) properties of SAR216471, a novel P2Y12 receptor antagonist. SAR216471 blocks the binding of 2MeSADP to P2Y12 receptors in vitro (IC50=17 nM). This inhibition was shown to be reversible. It potently antagonized ADP-induced platelet aggregation in human and rat platelet-rich plasma (IC50=108 and 62 nM, respectively). It also inhibited platelet aggregation when blood was exposed to collagen or thromboxane A2. Its high selectivity was demonstrated against a large panel of receptors, enzymes, and ion channels. Despite its moderate bioavailability in rats, oral administration of SAR216471 resulted in a fast, potent, and sustained inhibition of platelet aggregation where the extent and duration of platelet inhibition were directly proportional to its circulating plasma levels. Pre-clinical study of SAR216471 in a rat shunt thrombosis model demonstrated a dose-dependent antithrombotic activity after oral administration (ED50=6.7 mg/kg). By comparison, ED50 values for clopidogrel, prasugrel and ticagrelor were 6.3, 0.35 and 2.6 mg/kg, respectively. Finally, the anti-hemostatic effect of SAR216471 and its competitors was investigated in a rat tail bleeding model, revealing a favorable safety profile of SAR216471. Together, these findings have established a reliable antiplatelet profile of SAR216471, and support its potential use in clinical practice as an alternative to currently available P2Y12 receptor antagonists. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect