Small Molecule c-jun-N-Terminal Kinase Inhibitors Protect Dopaminergic Neurons in a Model of Parkinson’s Disease

There are currently no drugs to treat neurodegeneration in Parkinson’s disease (PD), and all existing medications only treat symptoms, lose efficacy over time, and produce untoward side effects. In the current work, we report the first highly selective, orally bioavailable c-jun-N-terminal kinase (J...

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Published in:ACS chemical neuroscience 2011-04, Vol.2 (4), p.198-206
Main Authors: Chambers, Jeremy W, Pachori, Alok, Howard, Shannon, Ganno, Michelle, Hansen, Donald, Kamenecka, Ted, Song, Xinyi, Duckett, Derek, Chen, Weimin, Ling, Yuan Yuan, Cherry, Lisa, Cameron, Michael D, Lin, Li, Ruiz, Claudia H, LoGrasso, Philip
Format: Article
Language:English
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Summary:There are currently no drugs to treat neurodegeneration in Parkinson’s disease (PD), and all existing medications only treat symptoms, lose efficacy over time, and produce untoward side effects. In the current work, we report the first highly selective, orally bioavailable c-jun-N-terminal kinase (JNK) inhibitor for protection of dopaminergic neurons in vitro and in vivo. At 300 nM, this compound showed statistically significant protection of primary dopaminergic neurons exposed to 1-methyl-4-phenylpyridinium (MPP+), had pharmacokinetic properties in rodents consistent with twice daily (b.i.d.) dosing, and was orally efficacious at 30 mg/kg in a mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of Parkinson’s disease. Moreover, a dose-dependent target modulation of c-jun phosphorylation served as a biomarker for demonstrating on-target inhibition of JNK as the mechanism of action for this compound. Collectively, these results suggest that this JNK inhibitor could be a promising therapeutic neuroprotective agent in the treatment of Parkinson’s disease.
ISSN:1948-7193
1948-7193
DOI:10.1021/cn100109k