1555696-37-1Relevant articles and documents
7-HYDROXY-INDOLINYL ANTAGONISTS OF P2Y1 RECEPTOR
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Paragraph 00279, (2014/02/16)
The present invention provides compounds of Formula (I): Formula (I) as defined in the specification and compositions comprising any of such novel compounds. These compounds are antagonists of P2Y1 receptor which may be used medicaments.
Discovery of 4-Aryl-7-hydroxyindoline-based P2Y1 antagonists as novel antiplatelet agents
Yang, Wu,Wang, Yufeng,Lai, Amy,Qiao, Jennifer X.,Wang, Tammy C.,Hua, Ji,Price, Laura A.,Shen, Hong,Chen, Xue-Qing,Wong, Pancras,Crain, Earl,Watson, Carol,Huang, Christine S.,Seiffert, Dietmar A.,Rehfuss, Robert,Wexler, Ruth R.,Lam, Patrick Y. S.
, p. 6150 - 6164 (2014/08/18)
Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y12 and P2Y1. Blocking P2Y12 receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y1 antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y12 inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y1 antagonist, 1. This paper describes further optimization of 1 by introducing 4-aryl groups at the hydroxylindoline in two series. In the neutral series, 10q was identified with excellent potency and desirable pharmacokinetic (PK) profile. It also demonstrated similar antithrombotic efficacy with less bleeding compared with the known P2Y 12 antagonist prasugrel in rabbit efficacy/bleeding models. In the basic series, 20c (BMS-884775) was discovered with an improved PK and liability profile over 1. These results support P2Y1 antagonism as a promising new antiplatelet target.
