Discovery of 1‑Difluoromethyl-3-(3-cyanophenyl)-6-[4-(trifluoromethoxy)phenyl]imidazo[1,5‑a]pyrazin-8-(7H)‑one as a Potent P2Y1 Antagonist for the Treatment of Ischemic Stroke and Myocardial Infarction

The P2Y1 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 P2Y1 antagonist HNW001. Compound 12g, containing an imidazo[1,5-a]pyrazine scaffold, turned out to be a remarkable P2Y1 antagonist (IC50 = 1.95 μM) with improved brain drug exposure (AUC(compound 12g) = 37.57 μg/g·h vs AUC(HNW001) = 6.65 μg/g·h) and less bleeding risk, and it also displayed great potential for neuroprotection. Subsequently, the anti-ischemic stroke efficacy of compound 12g was validated using a rat MCAO model (ED50 = 4.49 mg/kg), outperforming HNW001, BPTU, and edaravone. Additionally, compound 12g dose-dependently inhibited infarct sizes in a mouse myocardial infarction model. Collectively, these findings suggested that the imidazo[1,5-a]pyrazine scaffold has potential for developing effective P2Y1 antagonists, and compound 12g could be a promising anti-ischemic agent for treating ischemic stroke and myocardial infarction.