Discovery of N-(6-(5-fluoro-2-(piperidin-1-yl)phenyl)pyridazin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)methanesulfonamide as a brain-permeable and metabolically stable kynurenine monooxygenase inhibitor,Bioorganic & Medicinal Chemistry Letters

当前位置： X-MOL 学术 › Bioorg. Med. Chem. Lett. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of N-(6-(5-fluoro-2-(piperidin-1-yl)phenyl)pyridazin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)methanesulfonamide as a brain-permeable and metabolically stable kynurenine monooxygenase inhibitor
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2021-05-17 , DOI: 10.1016/j.bmcl.2021.128115
Katsunori Tsuboi ₁ , Hidenori Kimura ₁ , Yoshie Nakatsuji ₁ , Momoe Kassai ₁ , Yoko Deai ₁ , Yoshiaki Isobe ₁

Affiliation

Kynurenine monooxygenase (KMO) is expected to be a good drug target to treat Huntington’s disease (HD). This study presents the structure-activity relationship of pyridazine derivatives to find novel KMO inhibitors. The most promising compound 14 resolved the problematic issues of lead compound 1, i.e., metabolic instability and reactive metabolite-derived side-effects. Compound 14 exhibited high brain permeability and a long-lasting pharmacokinetics profile in monkeys, and neuroprotective kynurenic acid was increased by a single administration of 14 in R6/2 mouse brain. These results demonstrated 14 may be a potential drug candidate to treat HD.

中文翻译：

发现 N-(6-(5-fluoro-2-(piperid-1-yl)phenyl)pyridazin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)methanesulfonamide 作为脑渗透性和代谢稳定的犬尿氨酸单加氧酶抑制剂

犬尿氨酸单加氧酶 (KMO) 有望成为治疗亨廷顿病 (HD) 的良好药物靶点。本研究展示了哒嗪衍生物的构效关系，以寻找新型 KMO 抑制剂。最有前途的化合物14解决了先导化合物 1 的问题，即代谢不稳定性和反应性代谢物衍生的副作用。化合物14在猴子中表现出高脑渗透性和持久的药代动力学特征，在 R6/2 小鼠脑中单次给药14可增加神经保护性犬尿酸。这些结果表明14可能是治疗 HD 的潜在候选药物。

更新日期：2021-05-26

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南