title: 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: Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: nathalie.delesque-touchard@sanofi.com.
authors: N
authors: N
authors: Delesque-Touchard
authors: Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France; 10 rue Lacaussade, 09400 Tarascon sur Ariége, France. Electronic address: anne-marie31@hotmail.fr.
authors: A M
authors: AM
authors: Pflieger
authors: Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: Sandrine.Bonnet-Lignon@sanofi.com.
authors: S
authors: S
authors: Bonnet-Lignon
authors: Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: Laurence.Millet@sanofi.com.
authors: L
authors: L
authors: Millet
authors: Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: Veronique.Salel@sanofi.com.
authors: V
authors: V
authors: Salel
authors: Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: Christophe.Boldron@sanofi.com.
authors: C
authors: C
authors: Boldron
authors: Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: Gilbert.Lassalle@sanofi.com.
authors: G
authors: G
authors: Lassalle
authors: Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: Jean-Marc.Herbert@sanofi.com.
authors: J M
authors: JM
authors: Herbert
authors: Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France; 725 Chemin du Château d'Eau, 31600 Seysses, France. Electronic address: pierre.savi@hotmail.fr.
authors: P
authors: P
authors: Savi
authors: Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: Francoise.Bono@sanofi.com.
authors: F
authors: F
authors: Bono
mesh_terms: D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D001682:Biological Availability; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011485:Protein Binding; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011724:Pyridazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000097:blood / Q000187:drug effects*; D058925:Receptors, Purinergic P2Y12 / Q000097:blood / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D013873:Thionucleotides / Q000378:metabolism; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*; D014162:Transfection
chemical_list: D005343:Fibrinolytic Agents; D007211:Indoles; C000593223: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; C548576:P2RY12 protein, human; C553058:P2ry12 protein, rat; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D011724:Pyridazines; D018048:Receptors, Purinergic P2; D058925:Receptors, Purinergic P2Y12; D013873:Thionucleotides; C002480:methylthio-ADP; D000244:Adenosine Diphosphate
keywords: ADP; Acute Coronary Syndrome; Antiplatelet Agents; Platelet aggregation; Purinergic P2Y(12) Receptor; Thrombosis