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Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors

2013; Elsevier BV; Volume: 23; Issue: 7 Linguagem: Inglês

10.1016/j.bmcl.2013.02.041

1464-3405

Albert W. Garofalo, Marc Adler, Danielle L. Aubele, Elizabeth Brigham, David Chian, Maurizio Franzini, Erich Goldbach, Grace Kwong, Ruth Motter, Gary D. Probst, Kevin P. Quinn, Lany Ruslim, Hing L. Sham, Danny Tam, Pearl Tanaka, Anh P. Truong, Xiaocong M. Ye, Zhao Ren,

Banana Cultivation and Research

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.