c-jun-N-terminal-kinase 3 is (JNK 3) a mitogen-activated protein (MAP) kinase family member expressed primary in the brain that phosphorylates many substrates associated with Parkinson's disease including c-jun and Tau. In this study we set up biochemical and cell-based assays which were used to support medicinal chemistry efforts designed to develop highly potent selective JNK inhibitors which have good brain penetration, good drug metabolism and pharmacokinetic (DMPK) properties, and show in vivo efficacy in animal models of Parkinson's disease.  Nanomolar JNK3 inhibitors which had > 1000-fold selectivity over p38 were developed.  Moreover, compounds were developed which had plasma:brain ratios of 2:1 or even 1:1 with good DMPK properties in rat.  Furthermore, these compounds were shown to be efficacious in the 6-OHDA and MPTP animal models of Parkinson's disease.

Small molecule c-jun-N-terminal kinase (JNK) inhibitors protect dopaminergic neurons in models of Parkinson's disease

241st National Meeting (2011)

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