title: Design and synthesis of a novel, orally active, brain penetrant, tri-substituted thiophene based JNK inhibitor.
abstract: The SAR of a series of tri-substituted thiophene JNK3 inhibitors is described. By optimizing both the N-aryl acetamide region of the inhibitor and the 4-position of the thiophene we obtained single digit nanomolar compounds, such as 47, which demonstrated an in vivo effect on JNK activity when dosed orally in our kainic acid mouse model as measured by phospho-c-jun reduction.
authors.affiliation: Department of Chemical Sciences, Elan Pharmaceuticals, South San Francisco, CA 94080, USA. simeon.bowers@elan.com
authors.forename: Simeon
authors.initials: S
authors.lastname: Bowers
authors.forename: Anh P
authors.initials: AP
authors.lastname: Truong
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Neitz
authors.forename: Martin
authors.initials: M
authors.lastname: Neitzel
authors.forename: Gary D
authors.initials: GD
authors.lastname: Probst
authors.forename: Roy K
authors.initials: RK
authors.lastname: Hom
authors.forename: Brian
authors.initials: B
authors.lastname: Peterson
authors.forename: Robert A
authors.initials: RA
authors.lastname: Galemmo
authors.forename: Andrei W
authors.initials: AW
authors.lastname: Konradi
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Gergley
authors.initials: G
authors.lastname: Tóth
authors.forename: Hu
authors.initials: H
authors.lastname: Pan
authors.forename: Nanhua
authors.initials: N
authors.lastname: Yao
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Brigham
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Quinn
authors.forename: John-Michael
authors.initials: JM
authors.lastname: Sauer
authors.forename: Kyle
authors.initials: K
authors.lastname: Powell
authors.forename: Lany
authors.initials: L
authors.lastname: Ruslim
authors.forename: Zhao
authors.initials: Z
authors.lastname: Ren
authors.forename: Frédérique
authors.initials: F
authors.lastname: Bard
authors.forename: Ted A
authors.initials: TA
authors.lastname: Yednock
authors.forename: Irene
authors.initials: I
authors.lastname: Griswold-Prenner
mesh_terms: D000284:Administration, Oral; D001921:Brain / Q000378:metabolism*; D015195:Drug Design; D006860:Hydrogen Bonding; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D048670:MAP Kinase Kinase 4