title: GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor.
abstract: Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for some forms of Parkinson's disease. Here we report the discovery and characterization of 2-arylmethyloxy-5-subtitutent-N-arylbenzamides with potent LRRK2 activities exemplified by GSK2578215A which exhibits biochemical IC(50)s of around 10 nM against both wild-type LRRK2 and the G2019S mutant. GSK2578215A exhibits exceptionally high selectivity for LRRK2 across the kinome, substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.3-1.0 μM in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100mg/kg.
authors.affiliation: External Alliances & Development, R&D China, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, UK. alastair.d.reith@gsk.com
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Reith
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: Karamjit
authors.initials: K
authors.lastname: Jandu
authors.forename: Daniele
authors.initials: D
authors.lastname: Andreotti
authors.forename: Lucy
authors.initials: L
authors.lastname: Mensah
authors.forename: Pamela
authors.initials: P
authors.lastname: Dossang
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.forename: Jinwei
authors.initials: J
authors.lastname: Zhang
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
mesh_terms: D016475:3T3 Cells; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D040681:Structural Homology, Protein
chemical_list: D047428:Protein Kinase Inhibitors; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases