Identification of Novel Quinolin-2(1H)-ones as Phosphodiesterase 1 Inhibitors for the Treatment of Inflammatory Bowel Disease.
Identification of Novel Quinolin-2(1H)-ones as Phosphodiesterase 1 Inhibitors for the Treatment of Inflammatory Bowel Disease.
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DOI：
10.1021/acs.jmedchem.3c01044
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发表时间：
2023-08
影响因子：
7.3
通讯作者：
Bei Zhang;Yi-Yi Yang-Yi;Zheng Zhao;Runduo Liu;Lingyun Feng;Mei-Yan Jiang;Yijun Yuan;Shuheng Huang-Shuhe
中科院分区：
文献类型：
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作者：
Bei Zhang;Yi-Yi Yang-Yi;Zheng Zhao;Runduo Liu;Lingyun Feng;Mei-Yan Jiang;Yijun Yuan;Shuheng Huang-Shuhe
磷酸二酯酶1（PDE 1）是PDE超家族中的一个亚家族，能同时水解环磷酸腺苷和环磷酸鸟苷。目前，PDE 1抑制剂的数量相对较少，大大限制了它们的应用。本文中，合理设计了一系列新的喹啉-2（1H）-酮，导致化合物10 c对PDE 1C的IC 50为15 nM，对其他PDE具有高选择性，并且具有显著的安全性。此外，我们使用先导化合物10 c作为化学工具来探索PDE 1是否可以作为治疗炎症性肠病（IBD）的新的潜在靶点，IBD是一种缺乏有效治疗的慢性复发性胃肠道炎症疾病。我们的研究结果表明，给予10 c在葡聚糖硫酸钠诱导的小鼠模型中具有显著的抗IBD作用，并减轻炎症反应，表明PDE 1可以作为IBD的有效靶点。
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.