2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of 4-(Difluoromethyl)-1 H-imidazole-5-carboxylic Acids/4-(3-Cyanophenoxy)pyrimidine-5-carboxylic Acids as P2Y1 Receptor Antagonists for Ischemic Stroke Treatment

Design, Synthesis, and Biological Evaluation of 4-(Difluoromethyl)-1 H-imidazole-5-carboxylic Acids/4-(3-Cyanophenoxy)pyrimidine-5-carboxylic Acids as P2Y1 Receptor Antagonists for Ischemic Stroke Treatment

  • J Med Chem. 2025 Jun 12;68(11):10930-10952. doi: 10.1021/acs.jmedchem.4c03117.
Bing Zhang 1,  Jinxin Li 1,  Qi Li 2,  Qiuhua Li 1,  Ruyu Wang 2,  Dan Liu 3,  Xiwen Dai 1,  Qing Mao 1,  Xuefeng Fu 1,  Wenhao Zha 2,  Fengwei Lin 1,  Chengjun Wu 1,  Yanhua Mou 2,  Shaojie Wang 1
Affiliations

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: 40371931 DOI: 10.1021/acs.jmedchem.4c03117
Abstract

To develop effective agents for ischemic stroke, compounds 19 (IC50 = 0.49 μM) and 36b (IC50 = 0.50 μM), as analogues of our previously reported antiplatelet agent HNW001, were identified as potent P2Y1 receptor antagonists, which were superior to HNW001 and BPTU (IC50 = 4.07 and 2.50 μM, respectively). Notably, these two compounds showed remarkable neuroprotective potency against oxidative stress by upregulating nuclear Nrf2 protein levels in vitro. Additionally, compounds 19 and 36b demonstrated favorable blood-brain barrier penetration potential in rats, and the rat MCAO model showed that they could effectively reduce infarction sizes with ED50 values of 8.39 and 4.60 mg/kg, respectively. Meanwhile, they could remarkably ameliorate neurobehavioral function, brain water content, oxidative parameters, and hippocampal tissue damage following MCAO. Thus, compounds 19 and 36b were promising lead compounds for developing effective agents to treat ischemic stroke.

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