Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors
2013
Garofalo, Albert W. | Adler, Marc | Aubele, Danielle L. | Brigham, Elizabeth F. | Chian, David | Franzini, Maurizio | Goldbach, Erich | Kwong, Grace T. | Motter, Ruth | Probst, Gary D. | Quinn, Kevin P. | Ruslim, Lany | Sham, Hing L. | Tam, Danny | Tanaka, Pearl | Truong, Anh P. | Ye, Xiaocong M. | Ren, Zhao
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.
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