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.

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。