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Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors. 2013
Albert W Garofalo, and
Marc Adler, and
Danielle L Aubele, and
Elizabeth F Brigham, and
David Chian, and
Maurizio Franzini, and
Erich Goldbach, and
Grace T Kwong, and
Ruth Motter, and
Gary D Probst, and
Kevin P Quinn, and
Lany Ruslim, and
Hing L Sham, and
Danny Tam, and
Pearl Tanaka, and
Anh P Truong, and
Xiaocong M Ye, and
Zhao Ren
Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, USA. albertwgarofalo@gmail.com
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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Ruth Motter, and
Gary D Probst, and
Kevin P Quinn, and
Lany Ruslim, and
Hing L Sham, and
Danny Tam, and
Pearl Tanaka, and
Anh P Truong, and
Xiaocong M Ye, and
Zhao Ren
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Ruth Motter, and
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Grace T Kwong, and
Ruth Motter, and
Gary D Probst, and
Kevin P Quinn, and
Lany Ruslim, and
Hing L Sham, and
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Pearl Tanaka, and
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