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

被引：42

作者：

Boldron, Christophe ^{[1
]}

Besse, Angelina ^{[1
]}

Bordes, Marie-Francoise ^{[1
]}

Tissandie, Stephanie ^{[1
]}

Yvon, Xavier ^{[1
]}

Gau, Benjamin ^{[1
]}

Badorc, Alain ^{[1
]}

Rousseaux, Tristan ^{[1
]}

Barre, Guillaume ^{[1
]}

Meneyrol, Jerome ^{[1
]}

Zech, Gernot ^{[4
]}

Nazare, Marc ^{[5
]}

Fossey, Valerie ^{[2
]}

Pflieger, Anne-Marie ^{[1
]}

Bonnet-Lignon, Sandrine ^{[1
]}

Millet, Laurence ^{[1
]}

Briot, Christophe ^{[3
]}

Dol, Frederique ^{[1
]}

Herault, Jean-Pascal ^{[1
]}

Savi, Pierre ^{[1
]}

Lassalle, Gilbert ^{[1
]}

Delesque, Nathalie ^{[1
]}

Herbert, Jean-Marc ^{[1
]}

Bono, Francoise ^{[1
]}

机构：

[1] Sanofi R&D, F-31036 Toulouse, France

[2] Sanofi R&D, F-91385 Chilly Mazarin, France

[3] Sanofi R&D, F-34184 Montpellier, France

[4] Sanofi R&D, D-65926 Frankfurt, Germany

[5] Leibniz Inst Mol Pharmacol, AG Med Chem, D-13125 Berlin, Germany

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 17期

关键词：

P2Y(12) RECEPTOR ANTAGONIST; AROMATIC-AMINES; ADENOSINE-DIPHOSPHATE; ANTIPLATELET THERAPY; MUTAGENICITY; TICLOPIDINE; ELINOGREL; CARCINOGENS; PREVENTION; ARYLHYDROXYLAMINES;

D O I：

10.1021/jm500588w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：7293 / 7316

页数：24

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