title: Discovery of heterocyclic ureas as a new class of raf kinase inhibitors: identification of a second generation lead by a combinatorial chemistry approach.
abstract: Heterocyclic ureas, such as N-3-thienyl N'-aryl ureas, have been identified as novel inhibitors of raf kinase, a key mediator in the ras signal transduction pathway. Structure-activity relationships were established, and the potency of the screening hit was improved 10-fold to IC(50)=1.7 microM. A combinatorial synthesis approach enabled the identification of a breakthrough lead (IC(50)=0.54 microM) for a second generation series of heterocyclic urea raf kinase inhibitors.
authors.affiliation: Department of Chemistry Research, Bayer Research Center, 400 Morgan Lane, West Haven, CT 06516, USA. roger.smith.b@bayer.com
authors.forename: R A
authors.initials: RA
authors.lastname: Smith
authors.forename: J
authors.initials: J
authors.lastname: Barbosa
authors.forename: C L
authors.initials: CL
authors.lastname: Blum
authors.forename: M A
authors.initials: MA
authors.lastname: Bobko
authors.forename: Y V
authors.initials: YV
authors.lastname: Caringal
authors.forename: R
authors.initials: R
authors.lastname: Dally
authors.forename: J S
authors.initials: JS
authors.lastname: Johnson
authors.forename: M E
authors.initials: ME
authors.lastname: Katz
authors.forename: N
authors.initials: N
authors.lastname: Kennure
authors.forename: J
authors.initials: J
authors.lastname: Kingery-Wood
authors.forename: W
authors.initials: W
authors.lastname: Lee
authors.forename: T B
authors.initials: TB
authors.lastname: Lowinger
authors.forename: J
authors.initials: J
authors.lastname: Lyons
authors.forename: V
authors.initials: V
authors.lastname: Marsh
authors.forename: D H
authors.initials: DH
authors.lastname: Rogers
authors.forename: S
authors.initials: S
authors.lastname: Swartz
authors.forename: T
authors.initials: T
authors.lastname: Walling
authors.forename: H
authors.initials: H
authors.lastname: Wild
mesh_terms: D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D014508:Urea; D019908:Proto-Oncogene Proteins c-raf