1. Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors
- Author
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Kevin P. Quinn, Marc Adler, Gary Probst, Albert W. Garofalo, Anh P. Truong, Danny Tam, Erich Goldbach, Danielle L. Aubele, Maurizio Franzini, David Chian, Grace Kwong, Xiaocong M. Ye, Zhao Ren, Hing L. Sham, Lany Ruslim, Pearl Tanaka, Elizabeth F. Brigham, and Ruth Motter
- Subjects
Models, Molecular ,Clinical Biochemistry ,Pharmaceutical Science ,Mice, Transgenic ,Protein Serine-Threonine Kinases ,Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ,MAP3K7 ,Biochemistry ,MAP2K7 ,Mice ,Structure-Activity Relationship ,Drug Discovery ,Animals ,Humans ,c-Raf ,Kinase activity ,Protein Kinase Inhibitors ,Molecular Biology ,Mice, Knockout ,Dose-Response Relationship, Drug ,Molecular Structure ,biology ,Cyclin-dependent kinase 4 ,Chemistry ,Organic Chemistry ,Cyclin-dependent kinase 2 ,Protein kinase R ,nervous system diseases ,HEK293 Cells ,Mutation ,Quinolines ,biology.protein ,Molecular Medicine ,Cyclin-dependent kinase 9 - Abstract
Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with familial Parkinson’s disease (PD). The kinase activity of this complex protein is increased by pathogenic mutations. Inhibition of LRRK2 kinase activity has therefore emerged as a promising approach for the treatment of PD. Herein we report our findings on a series of 4-alkylamino-7-aryl-3-cyanoquinolines that exhibit kinase inhibitory activity against both wild type and G2019S mutant LRRK2. Activity was determined in both biochemical and cellular assays. Compound 14 was further evaluated in an in vivo pharmacodynamic study and found to significantly inhibit Ser935 phosphorylation after oral dosing.
- Published
- 2013
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