SAR216471, an alternative to the use of currently available P2Y₁₂ receptor inhibitors?

Abstract

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.

• Authors: N Delesque-Touchard, A M Pflieger, S Bonnet-Lignon, L Millet, V Salel, C Boldron, G Lassalle, J M Herbert, P Savi, F Bono
• Journal: Thrombosis research (Thromb Res) Vol. 134 Issue 3 Pg. 693-703 (Sep 2014) ISSN: 1879-2472 [Electronic] United States
• PMID: 25064036 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Fibrinolytic Agents
• Indoles
• N-(6-(4-butanoyl-5-methyl-1H-pyrazol-1-yl)pyridazin-3-yl)-5-chloro-1-(2-(4-methylpiperazin-1-yl)-2-oxoethyl)-1H-indole-3-carboxamide
• P2RY12 protein, human
• P2ry12 protein, rat
• Platelet Aggregation Inhibitors
• Purinergic P2Y Receptor Antagonists
• Pyridazines
• Receptors, Purinergic P2
• Receptors, Purinergic P2Y12
• Thionucleotides
• methylthio-ADP
• Adenosine Diphosphate

Topics

• Adenosine Diphosphate (analogs & derivatives, metabolism)
• Administration, Oral
• Animals
• Binding, Competitive
• Biological Availability
• Blood Platelets (drug effects, metabolism)
• CHO Cells
• Cricetulus
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Fibrinolytic Agents (administration & dosage, pharmacokinetics, pharmacology, toxicity)
• Hemorrhage (chemically induced)
• Humans
• Indoles (administration & dosage, pharmacokinetics, pharmacology, toxicity)
• Male
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (administration & dosage, pharmacokinetics, pharmacology, toxicity)
• Protein Binding
• Purinergic P2Y Receptor Antagonists (administration & dosage, pharmacokinetics, pharmacology, toxicity)
• Pyridazines (administration & dosage, pharmacokinetics, pharmacology, toxicity)
• Rats, Sprague-Dawley
• Receptors, Purinergic P2 (blood, drug effects)
• Receptors, Purinergic P2Y12 (blood, drug effects)
• Signal Transduction (drug effects)
• Thionucleotides (metabolism)
• Thrombosis (blood, prevention & control)
• Transfection