A brain-permeable inhibitor of the neurodegenerative disease target kynurenine 3-monooxygenase prevents accumulation of neurotoxic metabolites

Dysregulation of the kynurenine pathway (KP) leads to imbalances in neuroactive metabolites associated with the pathogenesis of several neurodegenerative disorders, including Huntington’s disease (HD). Inhibition of the enzyme kynurenine 3-monooxygenase (KMO) in the KP normalises these metabolic imbalances and ameliorates neurodegeneration and related phenotypes in several neurodegenerative disease models. KMO is thus a promising candidate drug target for these disorders, but known inhibitors are not brain permeable. Here, 19 new KMO inhibitors have been identified. One of these ( 1 ) is neuroprotective in a Drosophila HD model but is minimally brain penetrant in mice. The prodrug variant ( 1b ) crosses the blood–brain barrier, releases 1 in the brain, thereby lowering levels of 3-hydroxykynurenine, a toxic KP metabolite linked to neurodegeneration. Prodrug 1b will advance development of targeted therapies against multiple neurodegenerative and neuroinflammatory diseases in which KP likely plays a role, including HD, Alzheimer’s disease, and Parkinson’s disease. Kynurenine 3-monooxygenase (KMO) regulates levels of neuroactive kynurenine pathway metabolites associated with neurodegeneration. Its inhibition ameliorates disease phenotypes in animal models but current inhibitors are not brain permeable. Through structure-based virtual screening and compound synthesis, Zhang et al. now develop KMO inhibitors that can enter the rodent brain to modulate metabolism in this pathway.