Discovery of 2-(Phenoxypyridine)-3-phenylureas as Small Molecule P2Y1 Antagonists

Two distinct G protein-coupled purinergic receptors, P2Y(1) and P2Y(12), mediate ADP-driven platelet activation. The clinical effectiveness of P2Y(12) blockade is well established Recent preclinical data suggest that P2Y(1) and P2Y(12) inhibition provide equivalent antithrombotic efficacy, while targeting P2Y(1) has the potential for reduced bleeding liability. In this account, the discovery of a 2-(phenoxypyridine)-3-phenylurea chemotype that inhibited ADP mediated platelet aggregation in human blood samples is described Optimization of this series led to the identification of compound 16, 1-(2-(2-tert-butylphenoxy)pyridin-3-yl)-3-4-(trifluoromethoxy)phenylurea, which demonstrated a 68 +/- 7% thrombus weight reduction in an established rat arterial thrombosis model (10 mg/kg plus 10 mg/kg/h) while only prolonging cuticle and mesenteric bleeding times by 3.3- and 3.1-fold, respectively, in provoked rat bleeding time models. These results suggest that a P2Y(1) antagonist could potentially provide a safe and efficacious antithrombotic profile.