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.

2023-12-01·European Journal of Medicinal Chemistry

Discovery of benzamide-based PI3K/HDAC dual inhibitors with marked pro-apoptosis activity in lymphoma cells

Article

作者: Chen, Hua ; Zhang, Tao ; Chen, Yuxin ; Wang, Yuanze ; Hou, Baogeng ; Deng, Jingjing ; Hou, Xiaohan ; Li, Xiaoyang

Inhibition of PI3K and histone deacetylase (HDAC) activity simultaneously using a single molecule appears to be a promising approach for cancer treatment. Current PI3K/HDAC dual inhibitors commonly use hydroxamate moiety as zinc binding group, which lack HDAC isoform selectivity and have potential genotoxicity. In this study, a novel series of benzamide-based PI3K/HDAC dual inhibitors were rationally designed and synthesized. Representative compound PH14 showed potent inhibitory activity toward PI3Kα and HDAC3, with IC₅₀ values of 20.3 nM and 24.5 nM, respectively. This was further supported by the blockage of AKT phosphorylation and an increase in acetylated histone H3 levels in Western blot study. The advantage of simultaneously targeting PI3Kα and HDAC is not only reflected in the significant antiproliferative activity, but also in its ability to promote the apoptosis in Jeko-1 cells. Moreover, PH14 had weak inhibitory effects on CYP450 enzymes and hERG. In the pharmacokinetic study, the administration of 1 mg/kg of PH14 the administration of 1 mg/kg of PH14 resulted in a t_1/2 of 10 h and an AUC _(0-∞) of 2772 h ng/mL. Our study may provide ideas for the further development of novel HDAC/PI3K dual inhibitors.

100 项与 PH-14 相关的药物交易

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