The goal of this project is to develop a c-jun N-terminal kinase 2/3 (JNK2/3) inhibitor that may be used in thetreatment of neurodegeneration in Parkinson's disease (PD). Development of a drug that preventsdopaminergic neurodegeneration would be first in class for halting progression of the disease and a clinicalcomplement to existing medication used in symptomatic treatment of PD. We have assembled a team ofbiochemists, cell biologists, medicinal chemists, structural biologists, pharmacologists, analytical chemists,and behavioral pharmacologists with extensive pharmaceutical experience to execute this drug developmentprogram.
In Aim 1 (years 1-2) we will optimize JNK2/3 inhibitors to select a preclinical developmentcandidate. By the end of year 2 we anticipate having one or more compounds that: 1) are potent andselective JNK2/3 inhibitors, 2) promote primary dopaminergic neuronal survival, and 3) have goodpharmacokinetic properties and brain penetration.
This aim will be accomplished by utilizing medicinalchemistry and structure-based drug design supported by biochemical and cell-based assays, andpharmacokinetics to develop structure-activity-relationships (SAR). During Aim 2 (year 3) we willdemonstrate efficacy in MPTP-mouse models of PD for greater than or equal to three compounds,demonstrate lack of interaction with human CYP450s, and evaluate five to ten compounds in preliminarytoxicity studies. The reason for evaluating five to ten of our most promising compounds is to optimize thechance for clinical success and mitigate the risk of developing a single molecule that may fail indevelopment.
In Aim 3 (years 4-5) we will conduct Investigation New Drug enabling genotoxicity, safetypharmacology, and toxicology studies aimed at helping select a clinical candidate that has the best metabolicprofile and widest therapeutic index. Collectively these studies are intended at generating a lead clinicalcandidate (and back ups) that have sufficient data to meet Food and Drug Administration standards tosupport up through Phase II human clinical trials in Parkinson's disease.
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