title: Discovery of 4-alkylamino-7-aryl-3-cyanoquinoline LRRK2 kinase inhibitors.
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.
authors: Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd., South San Francisco, CA 94080, USA. albertwgarofalo@gmail.com
authors: Albert W
authors: AW
authors: Garofalo
authors: Marc
authors: M
authors: Adler
authors: Danielle L
authors: DL
authors: Aubele
authors: Elizabeth F
authors: EF
authors: Brigham
authors: David
authors: D
authors: Chian
authors: Maurizio
authors: M
authors: Franzini
authors: Erich
authors: E
authors: Goldbach
authors: Grace T
authors: GT
authors: Kwong
authors: Ruth
authors: R
authors: Motter
authors: Gary D
authors: GD
authors: Probst
authors: Kevin P
authors: KP
authors: Quinn
authors: Lany
authors: L
authors: Ruslim
authors: Hing L
authors: HL
authors: Sham
authors: Danny
authors: D
authors: Tam
authors: Pearl
authors: P
authors: Tanaka
authors: Anh P
authors: AP
authors: Truong
authors: Xiaocong M
authors: XM
authors: Ye
authors: Zhao
authors: Z
authors: Ren
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011804:Quinolines; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C495279:Lrrk2 protein, mouse; D017346:Protein Serine-Threonine Kinases