Discovery of 1-Difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethoxy)phenyl]imidazo[1,5-]pyrazin-8-(7)-one as a Potent P2Y Antagonist for the Treatment of Ischemic Stroke and Myocardial Infarction.

The P2Y receptor is a promising target for treating an ischemic stroke. Herein, a conformational restriction strategy was applied to improve the brain exposure of our previously reported P2Y antagonist HNW001. Compound , containing an imidazo[1,5-]pyrazine scaffold, turned out to be a remarkable P2Y antagonist (IC = 1.95 μM) with improved brain drug exposure (AUC = 37.57 μg/g·h vs AUC = 6.65 μg/gh) and less bleeding risk, and it also displayed great potential for neuroprotection. Subsequently, the anti-ischemic stroke efficacy of compound was validated using a rat MCAO model (ED = 4.49 mg/kg), outperforming HNW001, BPTU, and edaravone. Additionally, compound dose-dependently inhibited infarct sizes in a mouse myocardial infarction model. Collectively, these findings suggested that the imidazo[1,5-]pyrazine scaffold has potential for developing effective P2Y antagonists, and compound could be a promising anti-ischemic agent for treating ischemic stroke and myocardial infarction.