Switching a Xanthine Oxidase Inhibitor to a Dual-Target Antagonist of P2Y1 and P2Y12 as an Oral Antiplatelet Agent with a Wider Therapeutic Window in Rats than Ticagrelor

ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y₁ and P2Y₁₂ on the platelet. The clinical effectiveness of inhibiting P2Y₁₂ has been well established, and preclinical studies indicated that the inhibition of P2Y₁ could provide equivalent antithrombotic efficacy as P2Y₁₂ antagonists and reduce bleeding risks. On the basis of the 2-phenyl-1H-imidazole scaffold of our previously reported Xanthine Oxidase Inhibitor WSJ-557, we first achieved the transition from the Xanthine Oxidase inhibitors to dual-target antagonists against P2Y₁ and P2Y₁₂. We described the structure-activity relationships of the 2-phenyl-1H-imidazole compounds, which led to the identification of the most potent antiplatelet agents, 24w and 25w, both showing a rapid onset of action in pharmacokinetic study. Furthermore, the rat model suggested that 24w demonstrated a wider therapeutic window than ticagrelor, displaying equivalent and dose-dependent antithrombotic efficacy with lower blood loss compared to ticagrelor at same oral dose. These results supported that 24w and 25w could be promising drug candidates.