title: Potent P2Y1 urea antagonists bearing various cyclic amine scaffolds.
abstract: 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.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, Pennington, NJ 08534, USA. Electronic address: rejean.ruel@umontreal.ca.
authors.forename: Réjean
authors.initials: R
authors.lastname: Ruel
authors.forename: Alexandre
authors.initials: A
authors.lastname: L'Heureux
authors.forename: Carl
authors.initials: C
authors.lastname: Thibeault
authors.forename: Philippe
authors.initials: P
authors.lastname: Lapointe
authors.forename: Alain
authors.initials: A
authors.lastname: Martel
authors.forename: Jennifer X
authors.initials: JX
authors.lastname: Qiao
authors.forename: Ji
authors.initials: J
authors.lastname: Hua
authors.forename: Laura A
authors.initials: LA
authors.lastname: Price
authors.forename: Qimin
authors.initials: Q
authors.lastname: Wu
authors.forename: Ming
authors.initials: M
authors.lastname: Chang
authors.forename: Joanna
authors.initials: J
authors.lastname: Zheng
authors.forename: Christine S
authors.initials: CS
authors.lastname: Huang
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.forename: Robert
authors.initials: R
authors.lastname: Rehfuss
authors.forename: Patrick Y S
authors.initials: PY
authors.lastname: Lam
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D058912:Purinergic P2Y Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D058472:Receptors, Purinergic P2Y1 / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics
chemical_list: D000588:Amines; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D058912:Purinergic P2Y Receptor Agonists; D058472:Receptors, Purinergic P2Y1; D000244:Adenosine Diphosphate; C032727:piperidine; D014508:Urea
keywords: Isoindolines; P2Y(1) antagonists; Piperidines; Purinergic receptors; Tetrahydroisoquinolines