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

作者：Boldron Christophe^*; Besse Angelina; Bordes Marie Francoise; Tissandie Stephanie; Yvon Xavier; Gau Benjamin; Badorc Alain; Rousseaux Tristan; Barre Guillaume; Meneyrol Jerome; Zech Gernot; Nazare Marc; Fossey Valerie; Pflieger Anne Marie; Bonnet Lignon Sandrine; Millet Laurence; Briot Christophe; Dol Frederique; Herault Jean Pascal; Savi Pierre; Lassalle Gilbert; Delesque Nathalie; Herbert Jean Marc; Bono Francoise

来源：Journal of Medicinal Chemistry, 2014, 57(17): 7293-7316.

DOI：10.1021/jm500588w

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.

• 出版日期2014-9-11