2. Academic Validation
  3. Discovery of Isobenzofuran-1(3 H)-one Derivatives as Selective TREK-1 Inhibitors with In Vitro and In Vivo Neuroprotective Effects

Discovery of Isobenzofuran-1(3 H)-one Derivatives as Selective TREK-1 Inhibitors with In Vitro and In Vivo Neuroprotective Effects

  • J Med Chem. 2025 Mar 13;68(5):5804-5823. doi: 10.1021/acs.jmedchem.4c03146.
Kaiyue Liu 1,  Yunyun Ji 2,  Yiming Xie 2,  Chengyan Wang 1,  Jie Zhou 1,  Ziyi Wei 2,  Xiaoyu Wang 1,  Xiaotong Zheng 2,  Yao Cen 3,  Fan Zhang 2 4,  Bailing Xu 1
Affiliations

Affiliations

  • 1 Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 The Affiliated Nanjing Pukou Traditional Chinese Medicine Hospital, Jiangsu Provincial Key Laboratory for TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China.
  • 3 School of Pharmacy, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
  • 4 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Normal University, Guilin 541004, China.
PMID: 40040241 DOI: 10.1021/acs.jmedchem.4c03146
Abstract

TREK-1 regulates neuronal excitability and neuronal cell Apoptosis, and inhibition of TREK-1 is a potential strategy to prevent cell death and achieve neuroprotection in an ischemic stroke. In this work, a series of novel isobenzofuran-1(3H)-one derivatives were designed and synthesized as TREK-1 inhibitors, and extensive structure-activity relationships led to the discovery of potent and selective TREK-1 inhibitors having IC50 values of a low micromolar level. Among them, Cpd8l potently and selectively inhibited TREK-1 (IC50 = 0.81 μM, selectivity >30 fold over Other K+, Na+, and TRP channels). Cpd8l remarkably reduced the neuron death in the OGD/R-induced cortical neuronal injury model, while adenovirus silencing TREK-1 reduced its neuroprotective effect. Furthermore, Cpd8l could effectively ameliorate brain injury in MCAO/R model mice. Collectively, this work demonstrates that Cpd8l may serve as a novel lead compound to develop a highly potent and selective TREK-1 inhibitor for ischemic stroke treatment.

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