2. Academic Validation
  3. SAR216471, an alternative to the use of currently available P2Y₁₂ receptor inhibitors?

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

  • Thromb Res. 2014 Sep;134(3):693-703. doi: 10.1016/j.thromres.2014.06.034.
N Delesque-Touchard 1,  A M Pflieger 2,  S Bonnet-Lignon 3,  L Millet 4,  V Salel 5,  C Boldron 6,  G Lassalle 7,  J M Herbert 8,  P Savi 9,  F Bono 10
Affiliations

Affiliations

  • 1 Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: [email protected].
  • 2 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: [email protected].
  • 3 Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: [email protected].
  • 4 Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: [email protected].
  • 5 Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: [email protected].
  • 6 Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: [email protected].
  • 7 Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: [email protected].
  • 8 Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: [email protected].
  • 9 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: [email protected].
  • 10 Early to Candidate (E2C), Sanofi R&D, 195 Route d'Espagne, BP 13669, 31036 Toulouse, France. Electronic address: [email protected].
PMID: 25064036 DOI: 10.1016/j.thromres.2014.06.034
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.

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