RESUMO
Metabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Huntington/tratamento farmacológico , Ácido Cinurênico/análise , Quinurenina 3-Mono-Oxigenase/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Tiazóis/uso terapêutico , Administração Oral , Doença de Alzheimer/fisiopatologia , Animais , Química Encefálica , Modelos Animais de Doenças , Feminino , Humanos , Ácido Cinurênico/sangue , Masculino , Camundongos , Camundongos Transgênicos , Sulfonamidas/administração & dosagem , Tiazóis/administração & dosagemRESUMO
Efficient radical cyclization of alkyl iodides to various aromatic systems including pyrrole, indole, isoquinolone, pyridone, and benzene, mediated by dicumyl peroxide, is described. The methodology was used to provide access to 5,6,8,9,10,11-hexahydroindolo[2,1-a]isoquinoline derivatives.