title: Discovery of highly potent, selective, and brain-penetrant aminopyrazole leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors.
abstract: Leucine-rich repeat kinase 2 (LRRK2) has drawn significant interest in the neuroscience research community because it is one of the most compelling targets for a potential disease-modifying Parkinson's disease therapy. Herein, we disclose structurally diverse small molecule inhibitors suitable for assessing the implications of sustained in vivo LRRK2 inhibition. Using previously reported aminopyrazole 2 as a lead molecule, we were able to engineer structural modifications in the solvent-exposed region of the ATP-binding site that significantly improve human hepatocyte stability, rat free brain exposure, and CYP inhibition and induction liabilities. Disciplined application of established optimal CNS design parameters culminated in the rapid identification of GNE-0877 (11) and GNE-9605 (20) as highly potent and selective LRRK2 inhibitors. The demonstrated metabolic stability, brain penetration across multiple species, and selectivity of these inhibitors support their use in preclinical efficacy and safety studies.
authors.affiliation: Departments of †Discovery Chemistry, ‡Neurosciences, §Biochemical and Cellular Pharmacology, ∥Drug Metabolism and Pharmacokinetics, ⊥Safety Assessment, and #Structural Biology, Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, United States.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Estrada
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Chan
authors.forename: Charles
authors.initials: C
authors.lastname: Baker-Glenn
authors.forename: Alan
authors.initials: A
authors.lastname: Beresford
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Burdick
authors.forename: Mark
authors.initials: M
authors.lastname: Chambers
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.forename: Sara L
authors.initials: SL
authors.lastname: Dominguez
authors.forename: Jennafer
authors.initials: J
authors.lastname: Dotson
authors.forename: Jason
authors.initials: J
authors.lastname: Drummond
authors.forename: Michael
authors.initials: M
authors.lastname: Flagella
authors.forename: Reina
authors.initials: R
authors.lastname: Fuji
authors.forename: Andrew
authors.initials: A
authors.lastname: Gill
authors.forename: Jason
authors.initials: J
authors.lastname: Halladay
authors.forename: Seth F
authors.initials: SF
authors.lastname: Harris
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.forename: Tracy
authors.initials: T
authors.lastname: Kleinheinz
authors.forename: Donna W
authors.initials: DW
authors.lastname: Lee
authors.forename: Claire E
authors.initials: CE
authors.lastname: Le Pichon
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Lyssikatos
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Medhurst
authors.forename: John G
authors.initials: JG
authors.lastname: Moffat
authors.forename: Kevin
authors.initials: K
authors.lastname: Nash
authors.forename: Kimberly
authors.initials: K
authors.lastname: Scearce-Levie
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Sheng
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Shore
authors.forename: Susan
authors.initials: S
authors.lastname: Wong
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhang
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhu
authors.forename: Zachary K
authors.initials: ZK
authors.lastname: Sweeney
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C587728:2-methyl-2-(3-methyl-4-((4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)propanenitrile; C587729:N2-(5-chloro-1-(3-fluoro-1-(oxetan-3-yl)piperidin-4-yl)-1H-pyrazol-4-yl)-N4-methyl-5-(trifluoromethyl)pyrimidine-2,4-diamine; D011720:Pyrazoles; D011743:Pyrimidines; C495280:LRRK2 protein, human; C547428:LRRK2 protein, rat; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases