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

  • J Med Chem. 2025 Aug 28;68(16):17990-18015. doi: 10.1021/acs.jmedchem.5c01780.
Bing Zhang  1 ,  Jinxin Li  1 ,  Ruyu Wang  2 ,  Qi Li  2 ,  Qing Mao  1 ,  Xuefeng Fu  1 ,  Qingbo Song  1 ,  Dan Liu  3 ,  Xiwen Dai  1 ,  Zhulin Du  1 ,  Chang Liu  1 ,  Ziyuan Liu  1 ,  Xing Chen  1 ,  Chengjun Wu  1 ,  Yanhua Mou  2 ,  Shaojie Wang  1
Affiliations
  • 1. Key Laboratory of Structure-Based Drugs Design & Discovery of Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang 110016, China.
  • 2. Department of Pharmacology, Shenyang Pharmaceutical University, 103 Culture Road, Shenhe District, Shenyang 110016, China.
  • 3. Shenyang Hinewy Pharmaceutical Technology Co., Ltd. 41 Liutang Road, Shenhe District, Shenyang 110016, China.
PMID: 40767268 DOI: 10.1021/acs.jmedchem.5c01780
Abstract

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.

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