title: 1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3.
abstract: A series of 1-aryl-3,4-dihydroisoquinoline inhibitors of JNK3 are described. Compounds 20 and 24 are the most potent inhibitors (pIC50 7.3 and 6.9, respectively in a radiometric filter binding assay), with 10- and 1000-fold selectivity over JNK2 and JNK1, respectively, and selectivity within the wider mitogen-activated protein kinase (MAPK) family against p38alpha and ERK2. X-ray crystallography of 16 reveals a highly unusual binding mode where an H-bond acceptor interaction with the hinge region is made by a chloro substituent.
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre, Stevenage, Hertfordshire, UK. john@christopher257.fsnet.co.uk
authors.forename: John A
authors.initials: JA
authors.lastname: Christopher
authors.forename: Francis L
authors.initials: FL
authors.lastname: Atkinson
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Bax
authors.forename: Murray J B
authors.initials: MJ
authors.lastname: Brown
authors.forename: Aurélie C
authors.initials: AC
authors.lastname: Champigny
authors.forename: Tsu Tshen
authors.initials: TT
authors.lastname: Chuang
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Jones
authors.forename: Julie E
authors.initials: JE
authors.lastname: Mosley
authors.forename: James R
authors.initials: JR
authors.lastname: Musgrave
mesh_terms: D001665:Binding Sites / Q000502:physiology; D005454:Fluorescence Polarization / Q000379:methods; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology
chemical_list: C109853:G 1617; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D048057:Mitogen-Activated Protein Kinase 10; D048308:Mitogen-Activated Protein Kinase 14; D048055:Mitogen-Activated Protein Kinase 8