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J Med Chem. 2016 Jul 14;59(13):6169-86. doi: 10.1021/acs.jmedchem.6b00297. Epub 2016 Jul 5.

New 6-Aminoquinoxaline Derivatives with Neuroprotective Effect on Dopaminergic Neurons in Cellular and Animal Parkinson Disease Models.

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BioCIS, Université Paris-Sud, CNRS, Université Paris-Saclay , 92290 Châtenay-Malabry, France.
Institut du Cerveau et de la Moelle Epinière, Sorbonne Universités, Université Pierre et Marie Curie Paris 06, INSERM U1127, CNRS UMR7225 , 75013 Paris, France.


Parkinson's disease (PD) is a neurodegenerative disorder of aging characterized by motor symptoms that result from the loss of midbrain dopamine neurons and the disruption of dopamine-mediated neurotransmission. There is currently no curative treatment for this disorder. To discover druggable neuroprotective compounds for dopamine neurons, we have designed and synthesized a second-generation of quinoxaline-derived molecules based on structure-activity relationship studies, which led previously to the discovery of our first neuroprotective brain penetrant hit compound MPAQ (5c). Neuroprotection assessment in PD cellular models of our newly synthesized quinoxaline-derived compounds has led to the selection of a better hit compound, PAQ (4c). Extensive in vitro characterization of 4c showed that its neuroprotective action is partially attributable to the activation of reticulum endoplasmic ryanodine receptor channels. Most interestingly, 4c was able to attenuate neurodegeneration in a mouse model of PD, making this compound an interesting drug candidate for the treatment of this disorder.

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