Discovery of 4-Aryl-7-Hydroxyindoline-Based P2Y_1 Antagonists as Novel Antiplatelet Agents

摘要

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, 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 P2Y_1 antagonism as a promising new antiplatelet target.