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

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.