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

Adenosine diphosphate (ADP)-mediated platelet aggregation is signaled through two distinct G protein-coupled receptors (GPCR) on the platelet surface: P2Y(12) and P2Y(1). Blocking P2Y(12) receptor is a clinically well-validated strategy for antithrombotic therapy. P2Y(1) antagonists have been shown to have the potential to provide equivalent antithrombotic efficacy as P2Y(12) inhibitors with reduced bleeding in preclinical animal models. We have previously reported the discovery of a potent and orally bioavailable P2Y(1) antagonist, I. 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 P2Y(1) antagonism as a promising new antiplatelet target.