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.
Keywords:
ADP; Acute Coronary Syndrome; Antiplatelet Agents; Platelet aggregation; Purinergic P2Y(12) Receptor; Thrombosis.
Copyright © 2014 Elsevier Ltd. All rights reserved.
MeSH terms
-
Adenosine Diphosphate / analogs & derivatives
-
Adenosine Diphosphate / metabolism
-
Administration, Oral
-
Animals
-
Binding, Competitive
-
Biological Availability
-
Blood Platelets / drug effects*
-
Blood Platelets / metabolism
-
CHO Cells
-
Cricetulus
-
Disease Models, Animal
-
Dose-Response Relationship, Drug
-
Fibrinolytic Agents / administration & dosage
-
Fibrinolytic Agents / pharmacokinetics
-
Fibrinolytic Agents / pharmacology*
-
Fibrinolytic Agents / toxicity
-
Hemorrhage / chemically induced
-
Humans
-
Indoles / administration & dosage
-
Indoles / pharmacokinetics
-
Indoles / pharmacology*
-
Indoles / toxicity
-
Male
-
Platelet Aggregation / drug effects*
-
Platelet Aggregation Inhibitors / administration & dosage
-
Platelet Aggregation Inhibitors / pharmacokinetics
-
Platelet Aggregation Inhibitors / pharmacology*
-
Platelet Aggregation Inhibitors / toxicity
-
Protein Binding
-
Purinergic P2Y Receptor Antagonists / administration & dosage
-
Purinergic P2Y Receptor Antagonists / pharmacokinetics
-
Purinergic P2Y Receptor Antagonists / pharmacology*
-
Purinergic P2Y Receptor Antagonists / toxicity
-
Pyridazines / administration & dosage
-
Pyridazines / pharmacokinetics
-
Pyridazines / pharmacology*
-
Pyridazines / toxicity
-
Rats, Sprague-Dawley
-
Receptors, Purinergic P2 / blood
-
Receptors, Purinergic P2 / drug effects*
-
Receptors, Purinergic P2Y12 / blood
-
Receptors, Purinergic P2Y12 / drug effects*
-
Signal Transduction / drug effects
-
Thionucleotides / metabolism
-
Thrombosis / blood
-
Thrombosis / prevention & control*
-
Transfection
Substances
-
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