title: 3,5-Disubstituted-indole-7-carboxamides: the discovery of a novel series of potent, selective inhibitors of IKK-β.
abstract: The discovery and hit-to-lead exploration of a novel series of selective IKK-β kinase inhibitors is described. The initial lead fragment 3 was identified by pharmacophore-directed virtual screening. Homology model-driven SAR exploration of the template led to potent inhibitors, such as 12, which demonstrate efficacy in cellular assays and possess encouraging developability profiles.
authors.affiliation: GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK.
authors.forename: David D
authors.initials: DD
authors.lastname: Miller
authors.forename: Paul
authors.initials: P
authors.lastname: Bamborough
authors.forename: John A
authors.initials: JA
authors.lastname: Christopher
authors.forename: Ian R
authors.initials: IR
authors.lastname: Baldwin
authors.forename: Aurelie C
authors.initials: AC
authors.lastname: Champigny
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Cutler
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Kerns
authors.forename: Timothy
authors.initials: T
authors.lastname: Longstaff
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Mellor
authors.forename: James V
authors.initials: JV
authors.lastname: Morey
authors.forename: Mary A
authors.initials: MA
authors.lastname: Morse
authors.forename: Hong
authors.initials: H
authors.lastname: Nie
authors.forename: William L
authors.initials: WL
authors.lastname: Rumsey
authors.forename: John J
authors.initials: JJ
authors.lastname: Taggart
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D007211:Indoles; D047428:Protein Kinase Inhibitors; C030374:indole; D051550:I-kappa B Kinase