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
| Autor: | Laurence Millet, Angelina Besse, Stéphanie Tissandié, Gernot Zech, Marie-Francoise Bordes, Alain Badorc, Lassalle Gilbert, Valerie Fossey, Jean-Pascal Herault, Frédérique Dol, Christophe Boldron, Benjamin Gau, Christophe Briot, Nathalie Delesque, Anne-Marie Pflieger, Françoise Bono, Xavier Yvon, Marc Nazaré, Guillaume Barre, Tristan Rousseaux, Jean-Marc Herbert, Sandrine Bonnet-Lignon, Jerome Meneyrol, Pierre Savi |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Indoles Platelet Aggregation P2Y12 Receptor Antagonists medicine.drug_class Stereochemistry Administration Oral Carboxamide CHO Cells Binding Competitive Rats Sprague-Dawley P2Y12 Cricetulus In vivo Cricetinae Drug Discovery Antithrombotic medicine Purinergic P2 Receptor Antagonists Animals Humans Acute Coronary Syndrome Receptor Indole test Molecular Structure Chemistry Antagonist Thrombosis Receptors Purinergic P2Y12 Rats Adenosine Diphosphate Pyridazines Models Chemical Injections Intravenous Molecular Medicine Platelet Aggregation Inhibitors |
| Zdroj: | Journal of medicinal chemistry. 57(17) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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