2. Academic Validation
  3. Design, synthesis and activity evaluation of novel quinazolinone compounds as TRPC5 inhibitors

Design, synthesis and activity evaluation of novel quinazolinone compounds as TRPC5 inhibitors

  • Bioorg Chem. 2025 Feb:155:108147. doi: 10.1016/j.bioorg.2025.108147.
Longhui Bai 1,  Yu Xiang 2,  Meiling Shen 1,  Yujun Han 2,  Penghua Li 1,  Zhili Zuo 3,  Yang Li 4
Affiliations

Affiliations

  • 1 School of Pharmacology Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024 China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201 China; University of the Chinese Academy of Sciences, Beijing 100049 China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203 China.
  • 3 School of Pharmacology Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024 China; State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201 China; University of the Chinese Academy of Sciences, Beijing 100049 China. Electronic address: zlzuo@ucas.ac.cn.
  • 4 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203 China; University of the Chinese Academy of Sciences, Beijing 100049 China; National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai 200040 China. Electronic address: liyang@simm.ac.cn.
PMID: 39817997 DOI: 10.1016/j.bioorg.2025.108147
Abstract

The TRPC5 channel plays an important role in regulating various physiological processes, which is related to various human diseases, especially psychiatric and kidney diseases. Although the TRPC5 channel is one of the essential potential target, no drugs against TRPC5 channels have been granted in the market to date. In this study, based on the structure of hit compound ph1, we further synthesied 49 compounds of novel quinazolinone and heterocyclic fusion pyrimidinone derivatives, and their activities were evaluated by electrophysiological assays. After extensive screening, 21 compounds exhibited significant TRPC5 inhibitory activity, and compounds ph8 and ph14 displayed strong inhibitory with IC50 of 1.28 and 2.16 μM, respectively. These identified potential TRPC5 inhibitor may provide lead compounds and experimental evidence for the development of novel TRPC5 inhibitors with potential treatment for anxiety, depression, and progressive kidney disease.

Keywords

Activity evaluation; Inhibitors; Quinazolinone compounds; Structural modifications and optimizing; Synthesis; TRPC5.

Figures
Products