title: 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.
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.
authors: Sanofi R&D , 195 Route d'Espagne, 31036 Toulouse Cedex, France.
authors: Christophe
authors: C
authors: Boldron
authors: Angélina
authors: A
authors: Besse
authors: Marie-Françoise
authors: MF
authors: Bordes
authors: Stéphanie
authors: S
authors: Tissandié
authors: Xavier
authors: X
authors: Yvon
authors: Benjamin
authors: B
authors: Gau
authors: Alain
authors: A
authors: Badorc
authors: Tristan
authors: T
authors: Rousseaux
authors: Guillaume
authors: G
authors: Barré
authors: Jérôme
authors: J
authors: Meneyrol
authors: Gernot
authors: G
authors: Zech
authors: Marc
authors: M
authors: Nazare
authors: Valérie
authors: V
authors: Fossey
authors: Anne-Marie
authors: AM
authors: Pflieger
authors: Sandrine
authors: S
authors: Bonnet-Lignon
authors: Laurence
authors: L
authors: Millet
authors: Christophe
authors: C
authors: Briot
authors: Frédérique
authors: F
authors: Dol
authors: Jean-Pascal
authors: JP
authors: Hérault
authors: Pierre
authors: P
authors: Savi
authors: Gilbert
authors: G
authors: Lassalle
authors: Nathalie
authors: N
authors: Delesque
authors: Jean-Marc
authors: JM
authors: Herbert
authors: Françoise
authors: F
authors: Bono
mesh_terms: D054058:Acute Coronary Syndrome / Q000517:prevention & control; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D007275:Injections, Intravenous; D008297:Male; D008956:Models, Chemical; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D011724:Pyridazines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics / Q000378:metabolism*; D013927:Thrombosis / Q000517:prevention & control
chemical_list: D007211:Indoles; C000593223: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; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D011724:Pyridazines; D058925:Receptors, Purinergic P2Y12; D000244:Adenosine Diphosphate