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.
MeSH terms
-
Acute Coronary Syndrome / prevention & control
-
Adenosine Diphosphate / pharmacology
-
Administration, Oral
-
Animals
-
Binding, Competitive
-
CHO Cells
-
Cricetinae
-
Cricetulus
-
Humans
-
Indoles / chemical synthesis
-
Indoles / metabolism
-
Indoles / pharmacology*
-
Injections, Intravenous
-
Male
-
Models, Chemical
-
Molecular Structure
-
Platelet Aggregation / drug effects*
-
Platelet Aggregation Inhibitors / chemical synthesis
-
Platelet Aggregation Inhibitors / metabolism
-
Platelet Aggregation Inhibitors / pharmacology*
-
Purinergic P2 Receptor Antagonists / chemical synthesis
-
Purinergic P2 Receptor Antagonists / metabolism
-
Purinergic P2 Receptor Antagonists / pharmacology*
-
Pyridazines / chemical synthesis
-
Pyridazines / metabolism
-
Pyridazines / pharmacology*
-
Rats
-
Rats, Sprague-Dawley
-
Receptors, Purinergic P2Y12 / genetics
-
Receptors, Purinergic P2Y12 / metabolism*
-
Thrombosis / prevention & control
Substances
-
Indoles
-
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
-
Platelet Aggregation Inhibitors
-
Purinergic P2 Receptor Antagonists
-
Pyridazines
-
Receptors, Purinergic P2Y12
-
Adenosine Diphosphate