Discovery of novel indolinone-based, potent, selective and brain penetrant inhibitors of LRRK2

Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common genetic cause of Parkinson’s disease (PD). The most frequent kinase-enhancing mutation is the G2019S residing in the kinase activation domain. This opens up a promising therapeutic avenue for drug discovery targeting the kinase ac...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2013-07, Vol.23 (14), p.4085-4090
Main Authors: Troxler, Thomas, Greenidge, Paulette, Zimmermann, Kaspar, Desrayaud, Sandrine, Drückes, Peter, Schweizer, Tatjana, Stauffer, Daniela, Rovelli, Giorgio, Shimshek, Derya R.
Format: Article
Language:English
Subjects:
Animals
brain
Brain - metabolism
Cell Line
chemistry
Drug Evaluation, Preclinical
drugs
Half-Life
Indoles - chemistry
Indoles - metabolism
Indoles - pharmacokinetics
Kinase inhibitors
Leucine-rich repeat kinase 2
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
LRRK2
LRRK2 inhibitors
Mice
Mutation
Parkinson disease
Parkinson’s disease
Protein Binding
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - metabolism
Protein Kinase Inhibitors - pharmacokinetics
Protein-Serine-Threonine Kinases - antagonists & inhibitors
Protein-Serine-Threonine Kinases - genetics
Protein-Serine-Threonine Kinases - metabolism
Structure-Activity Relationship
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Summary:Mutations in leucine-rich repeat kinase-2 (LRRK2) are the most common genetic cause of Parkinson’s disease (PD). The most frequent kinase-enhancing mutation is the G2019S residing in the kinase activation domain. This opens up a promising therapeutic avenue for drug discovery targeting the kinase activity of LRRK2 in PD. Several LRRK2 inhibitors have been reported to date. Here, we report a selective, brain penetrant LRRK2 inhibitor and demonstrate by a competition pulldown assay in vivo target engagement in mice.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2013.05.054