Discovery of 4-Aryl-7-Hydroxyindoline-Based P2Y1 Antagonists as Novel Antiplatelet Agents

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• 作者：Wu Yang ; Yufeng Wang ; Amy Lai ; Jennifer X. Qiao ; Tammy C. Wang ; Ji Hua ; Laura A. Price ; Hong Shen ; Xue-qing Chen ; Pancras Wong ; Earl Crain ; Carol Watson ; Christine S. Huang ; Dietmar A. Seiffert ; Robert Rehfuss ; Ruth R. Wexler ; Patrick Y. S. Lam
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：July 24, 2014
• 年：2014
• 卷：57
• 期：14
• 页码：6150-6164
• 全文大小：611K
• ISSN：1520-4804

文摘

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 P2Y₁₂ 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.