title: Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors.
abstract: There is a high demand for potent, selective, and brain-penetrant small molecule inhibitors of leucine-rich repeat kinase 2 (LRRK2) to test whether inhibition of LRRK2 kinase activity is a potentially viable treatment option for Parkinson's disease patients. Herein we disclose the use of property and structure-based drug design for the optimization of highly ligand efficient aminopyrimidine lead compounds. High throughput in vivo rodent cassette pharmacokinetic studies enabled rapid validation of in vitro-in vivo correlations. Guided by this data, optimal design parameters were established. Effective incorporation of these guidelines into our molecular design process resulted in the discovery of small molecule inhibitors such as GNE-7915 (18) and 19, which possess an ideal balance of LRRK2 cellular potency, broad kinase selectivity, metabolic stability, and brain penetration across multiple species. Advancement of GNE-7915 into rodent and higher species toxicity studies enabled risk assessment for early development.
authors.affiliation: Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. anthony@gene.com
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Estrada
authors.forename: Xingrong
authors.initials: X
authors.lastname: Liu
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: Bryan K
authors.initials: BK
authors.lastname: Chan
authors.forename: Huifen
authors.initials: H
authors.lastname: Chen
authors.forename: Xiao
authors.initials: X
authors.lastname: Ding
authors.forename: Antonio G
authors.initials: AG
authors.lastname: DiPasquale
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: Sean
authors.initials: S
authors.lastname: Flynn
authors.forename: Reina
authors.initials: R
authors.lastname: Fuji
authors.forename: Andrew
authors.initials: A
authors.lastname: Gill
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner-Toste
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: 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: Susmith
authors.initials: S
authors.lastname: Mukund
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: Thuy
authors.initials: T
authors.lastname: Tran
authors.forename: Naimisha
authors.initials: N
authors.lastname: Trivedi
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.forename: Shuo
authors.initials: S
authors.lastname: Zhang
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.forename: Guiling
authors.initials: G
authors.lastname: Zhao
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*; D015195:Drug Design; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008252:Macaca fascicularis; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009025:Morpholines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D054852:Small Molecule Libraries; D014018:Tissue Distribution
chemical_list: C577934:(4-(4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-2-fluoro-5-methoxyphenyl)(morpholino)methanone; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D054852:Small Molecule Libraries; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases