Identification of Novel Quinolin-2(1<i>H</i>)-ones as Phosphodiesterase 1 Inhibitors for the Treatment of Inflammatory Bowel Disease
Bei Zhang, Yiyi Yang, Zheng-Jiong Zhao, Runduo Liu, Lingling Feng, Mei-Yan Jiang, Yijun Yuan, Shuheng Huang, Zhe Li, Quan Wang, Hai‐Bin Luo, Yinuo Wu
Abstract
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(1 H )-ones were designed rationally, leading to compound 10c with an IC 50 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.