2. Academic Validation
  3. Discovery of 2,4-Disubstituted Pyrimidine Derivatives as Novel Kir4.1 Inhibitors with Rapid-Onset Antidepressant Effect

Discovery of 2,4-Disubstituted Pyrimidine Derivatives as Novel Kir4.1 Inhibitors with Rapid-Onset Antidepressant Effect

  • J Med Chem. 2026 Jan 22;69(2):1606-1627. doi: 10.1021/acs.jmedchem.5c03092.
Sisi Wang 1,  Mengdan Li 2 3,  Chao Zhang 1,  Haiyan Xu 2,  Jingyi He 2,  Yunpeng Guo 1,  Hao Gu 1,  Li Zhan 2,  Yongjie Cai 2,  Tianyu Tu 1,  Jian Li 1 4 5,  Zhaobing Gao 2 3 6,  Xiaoyu Zhou 2,  Yixiang Xu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 School of Pharmacy, Henan University, Kaifeng 475004, China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 5 Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China.
  • 6 Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528437, China.
PMID: 41498564 DOI: 10.1021/acs.jmedchem.5c03092
Abstract

Depression is a major global health threat and necessitates novel rapid-acting and safe antidepressants. Targeting astrocytic Kir4.1 in the lateral habenula has been identified as a potential therapy strategy for depression with rapid-onset effects. Our research aims to develop novel and potent Kir4.1 inhibitors with good druggability through structural modification based on the lead compound EHop-016, resulting in 37 2,4-disubstituted pyrimidine derivatives. Among these, compound 37 demonstrated potent Kir4.1 inhibitory activity (IC50 = 0.19 μM), acceptable Kir subtype selectivity, favorable pharmacokinetic properties, and safety. Notably, compound 37 exhibited rapid-onset antidepressant effects within 1 h in the novelty-suppressed feeding test at a dosage three times lower than that of EHop-016. These findings establish 37 as a potent and selective Kir4.1 inhibitor with rapid antidepressant efficacy and good druggability, supporting its further development for depression treatment.

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