Discovery of 4-aryl-7-hydroxyindoline-based P2Y1 antagonists as novel antiplatelet agents

  • J Med Chem. 2014 Jul 24;57(14):6150-64. doi: 10.1021/jm5006226.
Wu Yang  1 ,  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
Affiliations
  • 1. Discovery Chemistry, ‡Discovery Biology, and §Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research , Post Office Box 5400, Princeton, New Jersey 08643-5400, United States.
PMID: 24931384 DOI: 10.1021/jm5006226
Abstract

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.

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