Identification of Novel Quinolin-2(1H)-ones as Phosphodiesterase 1 Inhibitors for the Treatment of Inflammatory Bowel Disease

被引:8
作者
Zhang, Bei [1 ]
Yang, Yi-Yi [1 ]
Zhao, Zheng-Jiong [1 ]
Liu, Run-Duo [1 ]
Feng, Ling-Ling [1 ]
Jiang, Mei-Yan [1 ]
Yuan, Yijun [2 ]
Huang, Shuheng [2 ]
Li, Zhe [1 ]
Wang, Quan [1 ]
Luo, Hai-Bin [1 ,2 ,3 ]
Wu, Yinuo [1 ]
机构
[1] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Peoples R China
[2] Hainan Univ, Sch Life & Pharmaceut Sci, Key Lab Trop Biol Resources, Minist Educ, Haikou 570228, Hainan, Peoples R China
[3] Hainan Univ, Sch Pharmaceut Sci, Song Li Academician Workstat, Sanya 572000, Peoples R China
关键词
DISCOVERY;
D O I
10.1021/acs.jmedchem.3c01044
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Phosphodiesterase 1 (PDE1) is a subfamily of PDE superenzyme familiesthat can hydrolyze cyclic adenosine monophosphate and cyclic guanosinemonophosphate simultaneously. Currently, the number of PDE1 inhibitorsis relatively few, significantly limiting their application. Herein,a novel series of quinolin-2(1H)-ones were designedrationally, leading to compound 10c with an IC50 of 15 nM against PDE1C, high selectivity across other PDEs, andremarkable safety properties. Furthermore, we used the lead compound 10c as a chemical tool to explore whether PDE1 could workas a novel potential target for the treatment of inflammatory boweldisease (IBD), a disease which is a chronic, relapsing disorder ofthe gastrointestinal tract inflammation lacking effective treatment.Our results showed that administration of 10c exertedsignificant anti-IBD effects in the dextran sodium sulfate-inducedmice model and alleviated the inflammatory response, indicating thatPDE1 could work as a potent target for IBD.
引用
收藏
页码:12468 / 12478
页数:11
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