Potent P2Y1 urea antagonists bearing various cyclic amine scaffolds

A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-12, Vol.23 (24), p.6825-6828
Hauptverfasser:	Ruel, Réjean, L’Heureux, Alexandre, Thibeault, Carl, Lapointe, Philippe, Martel, Alain, Qiao, Jennifer X., Hua, Ji, Price, Laura A., Wu, Qimin, Chang, Ming, Zheng, Joanna, Huang, Christine S., Wexler, Ruth R., Rehfuss, Robert, Lam, Patrick Y.S.
Format:	Artikel
Sprache:	eng
Schlagworte:	Adenosine Diphosphate - pharmacology Amines - chemical synthesis Amines - chemistry Amines - pharmacokinetics Animals Antagonists Blood Platelets - drug effects Blood Platelets - metabolism Half-Life Humans Isoindolines Microsomes, Liver - metabolism P2Y1 antagonists Piperidines Piperidines - chemistry platelet aggregation Platelet Aggregation Inhibitors - chemical synthesis Platelet Aggregation Inhibitors - chemistry Platelet Aggregation Inhibitors - pharmacokinetics Protein Binding Purinergic P2Y Receptor Agonists - chemical synthesis Purinergic P2Y Receptor Agonists - chemistry Purinergic P2Y Receptor Agonists - pharmacokinetics Purinergic receptors Rats Receptors, Purinergic P2Y1 - chemistry Receptors, Purinergic P2Y1 - metabolism solubility Structure-Activity Relationship Tetrahydroisoquinolines urea Urea - analogs & derivatives Urea - chemical synthesis Urea - pharmacokinetics
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Zusammenfassung:	A number of new amine scaffolds with good inhibitory activity in the ADP-induced platelet aggregation assay have been found to be potent antagonists of the P2Y1 receptor. SAR optimization led to the identification of isoindoline 3c and piperidine 4a which showed good in vitro binding and functional activities, as well as improved aqueous solubility. Among them, the piperidine 4a showed the best overall profile with favorable PK parameters.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.10.009