title: Novel cinnoline-based inhibitors of LRRK2 kinase activity.
abstract: Leucine rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson's disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of cinnoline-3-carboxamides that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays. These compounds are also shown to be potent inhibitors in a cellular assay and to have good to excellent CNS penetration.
authors.affiliation: Department of Medicinal Chemistry, Elan Pharmaceuticals, 180 Oyster Point Blvd, South San Francisco, CA 94080, United States. albert.garofalo@elan.com
authors.forename: Albert W
authors.initials: AW
authors.lastname: Garofalo
authors.forename: Marc
authors.initials: M
authors.lastname: Adler
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Aubele
authors.forename: Simeon
authors.initials: S
authors.lastname: Bowers
authors.forename: Maurizio
authors.initials: M
authors.lastname: Franzini
authors.forename: Erich
authors.initials: E
authors.lastname: Goldbach
authors.forename: Colin
authors.initials: C
authors.lastname: Lorentzen
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.forename: Gary D
authors.initials: GD
authors.lastname: Probst
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.forename: Pam
authors.initials: P
authors.lastname: Santiago
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Danny
authors.initials: D
authors.lastname: Tam
authors.forename: Anh P
authors.initials: AP
authors.lastname: Truong
authors.forename: Xiaocong M
authors.initials: XM
authors.lastname: Ye
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ren
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D057809:HEK293 Cells; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry*; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D014162:Transfection
chemical_list: D000577:Amides; D006574:Heterocyclic Compounds, 2-Ring; D047428:Protein Kinase Inhibitors; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases; C476282:cinnoline