化学
炎症性肠病
磷酸二酯酶
鸟苷
药理学
酶
炎症
环磷酸鸟苷
生物化学
疾病
免疫学
内科学
医学
有机化学
一氧化氮
作者
Bei Zhang,Yiyi Yang,Zhixiang Zhao,Runduo Liu,Lingling Feng,Meiyan Jiang,Yijun Yuan,Shuheng Huang,Zhe Li,Quan Wang,Hai‐Bin Luo,Yinuo Wu
标识
DOI:10.1021/acs.jmedchem.3c01044
摘要
Phosphodiesterase 1 (PDE1) is a subfamily of PDE super enzyme families that can hydrolyze cyclic adenosine monophosphate and cyclic guanosine monophosphate simultaneously. Currently, the number of PDE1 inhibitors is relatively few, significantly limiting their application. Herein, a novel series of quinolin-2(1H)-ones were designed rationally, leading to compound 10c with an IC50 of 15 nM against PDE1C, high selectivity across other PDEs, and remarkable safety properties. Furthermore, we used the lead compound 10c as a chemical tool to explore whether PDE1 could work as a novel potential target for the treatment of inflammatory bowel disease (IBD), a disease which is a chronic, relapsing disorder of the gastrointestinal tract inflammation lacking effective treatment. Our results showed that administration of 10c exerted significant anti-IBD effects in the dextran sodium sulfate-induced mice model and alleviated the inflammatory response, indicating that PDE1 could work as a potent target for IBD.
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