title: N-(3-Cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amides as potent, selective, inhibitors of JNK2 and JNK3.
abstract: The identification and exploration of a novel, potent and selective series of N-(3-cyano-4,5,6,7-tetrahydro-1-benzothien-2-yl)amide inhibitors of JNK2 and JNK3 kinases is described. Compounds 5a and 11a were identified as potent inhibitors of JNK3 (pIC50 6.7 and 6.6, respectively), with essentially equal potency against JNK2 (pIC50 6.5). Selectivity within the mitogen-activated protein kinase (MAPK) family, against JNK1, p38alpha and ERK2, was observed for the series. X-ray crystallography of 5e and 8a in JNK3 revealed a unique binding mode, with the 3-cyano substituent forming an H-bond acceptor interaction with the hinge region of the ATP-binding site.
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Angell
authors.forename: Francis L
authors.initials: FL
authors.lastname: Atkinson
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Brown
authors.forename: Tsu Tshen
authors.initials: TT
authors.lastname: Chuang
authors.forename: John A
authors.initials: JA
authors.lastname: Christopher
authors.forename: Maria
authors.initials: M
authors.lastname: Cichy-Knight
authors.forename: Allison K
authors.initials: AK
authors.lastname: Dunn
authors.forename: Kendra E
authors.initials: KE
authors.lastname: Hightower
authors.forename: Susanna
authors.initials: S
authors.lastname: Malkakorpi
authors.forename: James R
authors.initials: JR
authors.lastname: Musgrave
authors.forename: Margarete
authors.initials: M
authors.lastname: Neu
authors.forename: Paul
authors.initials: P
authors.lastname: Rowland
authors.forename: Robyn L
authors.initials: RL
authors.lastname: Shea
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Smith
authors.forename: Donald O
authors.initials: DO
authors.lastname: Somers
authors.forename: Sonia A
authors.initials: SA
authors.lastname: Thomas
authors.forename: Gladstone
authors.initials: G
authors.lastname: Thompson
authors.forename: Ruolan
authors.initials: R
authors.lastname: Wang
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D048056:Mitogen-Activated Protein Kinase 9 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D001555:Benzene Derivatives; D048057:Mitogen-Activated Protein Kinase 10; D048056:Mitogen-Activated Protein Kinase 9