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 (SAR216471), a novel intravenous and oral, reversible, and directly acting P2Y12 antagonist

  • J Med Chem. 2014 Sep 11;57(17):7293-316. doi: 10.1021/jm500588w.
Christophe Boldron  1 ,  Angélina Besse ,  Marie-Françoise Bordes ,  Stéphanie Tissandié ,  Xavier Yvon ,  Benjamin Gau ,  Alain Badorc ,  Tristan Rousseaux ,  Guillaume Barré ,  Jérôme Meneyrol ,  Gernot Zech ,  Marc Nazare ,  Valérie Fossey ,  Anne-Marie Pflieger ,  Sandrine Bonnet-Lignon ,  Laurence Millet ,  Christophe Briot ,  Frédérique Dol ,  Jean-Pascal Hérault ,  Pierre Savi ,  Gilbert Lassalle ,  Nathalie Delesque ,  Jean-Marc Herbert ,  Françoise Bono
Affiliations
  • 1. Sanofi R&D , 195 Route d'Espagne, 31036 Toulouse Cedex, France.
PMID: 25075638 DOI: 10.1021/jm500588w
Abstract

In the search of a potential backup for clopidogrel, we have initiated a HTS campaign designed to identify novel reversible P2Y12 antagonists. Starting from a hit with low micromolar binding activity, we report here the main steps of the optimization process leading to the identification of the preclinical candidate SAR216471. It is a potent, highly selective, and reversible P2Y12 Receptor Antagonist and by far the most potent inhibitor of ADP-induced platelet aggregation among the P2Y12 antagonists described in the literature. SAR216471 displays potent in vivo antiplatelet and antithrombotic activities and has the potential to differentiate from Other antiplatelet agents.

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