RESUMEN
The nuclear receptor, Nurr1, is critical for both the development and maintenance of midbrain dopamine neurons, representing a promising molecular target for Parkinson's disease (PD). We previously identified three Nurr1 agonists (amodiaquine, chloroquine and glafenine) that share an identical chemical scaffold, 4-amino-7-chloroquinoline (4A7C), suggesting a structure-activity relationship. Herein we report a systematic medicinal chemistry search in which over 570 4A7C-derivatives were generated and characterized. Multiple compounds enhance Nurr1's transcriptional activity, leading to identification of an optimized, brain-penetrant agonist, 4A7C-301, that exhibits robust neuroprotective effects in vitro. In addition, 4A7C-301 protects midbrain dopamine neurons in the MPTP-induced male mouse model of PD and improves both motor and non-motor olfactory deficits without dyskinesia-like behaviors. Furthermore, 4A7C-301 significantly ameliorates neuropathological abnormalities and improves motor and olfactory dysfunctions in AAV2-mediated α-synuclein-overexpressing male mouse models. These disease-modifying properties of 4A7C-301 may warrant clinical evaluation of this or analogous compounds for the treatment of patients with PD.
Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Ratones , Animales , Masculino , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/patología , Neuronas Dopaminérgicas/metabolismo , Mesencéfalo/metabolismo , Encéfalo/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Modelos Animales de Enfermedad , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismoRESUMEN
A five year old boy, weighing 14 kg with no family history of diabetes, presented in frank diabetic ketoacidosis. He recovered, but continued to have episodes of ketoacidosis. He was diagnosed to have biliary sludge, which recovered with insulin treatment.