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, Rev

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• 作者：Christophe Boldron ; Ang茅lina Besse ; Marie-Fran莽oise Bordes ; St茅phanie Tissandi茅 ; Xavier Yvon ; Benjamin Gau ; Alain Badorc ; Tristan Rousseaux ; Guillaume Barr茅 ; J茅r么me Meneyrol ; Gernot Zech ; Marc Nazare ; Val茅rie Fossey ; Anne-Marie Pflieger ; Sandrine Bonnet-Lignon ; Laurence Millet ; Christophe Briot ; Fr茅d茅rique Dol ; Jean-Pascal H茅rault ; Pierre Savi ; Gilbert Lassalle ; Nathalie Delesque ; Jean-Marc Herbert ; Fran莽oise Bono
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：September 11, 2014
• 年：2014
• 卷：57
• 期：17
• 页码：7293-7316
• 全文大小：1267K
• ISSN：1520-4804

文摘

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.