Kynurenine-3-monooxygenase (KMO) is an important therapeutic target for several brain disorders that has been extensively studied in recent years. Potent inhibitors towards KMO have been developed and tested within different disease models, showing great therapeutic potential, especially in models of neurodegenerative disease. The inhibition of KMO reduces the production of downstream toxic kynurenine pathway metabolites and shifts the flux to the formation of the neuroprotectant kynurenic acid. However, the efficacy of KMO inhibitors in neurodegenerative disease has been limited by their poor brain permeability. Combined with virtual screening and prodrug strategies, a novel brain penetrating KMO inhibitor has been developed which dramatically decreases neurotoxic metabolites. This review highlights the importance of KMO as a drug target in neurological disease and the benefits of brain permeable inhibitors in modulating kynurenine pathway metabolites in the central nervous system.

犬尿氨酸-3-单加氧酶 (KMO) 是近年来广泛研究的几种脑部疾病的重要治疗靶点。已经开发出针对 KMO 的强效抑制剂并在不同的疾病模型中进行了测试，显示出巨大的治疗潜力，尤其是在神经退行性疾病模型中。KMO 的抑制减少了下游有毒犬尿氨酸途径代谢物的产生，并将通量转移到神经保护剂犬尿酸的形成。然而，KMO 抑制剂在神经退行性疾病中的疗效受到其较差的脑通透性的限制。结合虚拟筛选和前药策略，已开发出一种新型脑穿透 KMO 抑制剂，可显着降低神经毒性代谢物。