title: The discovery of thienopyridine analogues as potent IkappaB kinase beta inhibitors. Part II.
abstract: An SAR study that identified a series of thienopyridine-based potent IkappaB Kinase beta (IKKbeta) inhibitors is described. With focuses on the structural optimization at C4 and C6 of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C4, whereas polar groups with proper orientation at C6 efficiently enhance compound potency. The most potent analogues inhibit IKKbeta with IC50s as low as 40 nM, suppress LPS-induced TNF-alpha production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-kappaB reporter gene assay, demonstrating that they directly interfere with the NF-kappaB signaling pathway.
authors.affiliation: Research and Development, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, CT 06877, United States. jiang_ping.wu@boehringer-ingelheim.com
authors.forename: Jiang-Ping
authors.initials: JP
authors.lastname: Wu
authors.forename: Roman
authors.initials: R
authors.lastname: Fleck
authors.forename: Janice
authors.initials: J
authors.lastname: Brickwood
authors.forename: Alison
authors.initials: A
authors.lastname: Capolino
authors.forename: Katrina
authors.initials: K
authors.lastname: Catron
authors.forename: Zhidong
authors.initials: Z
authors.lastname: Chen
authors.forename: Charles
authors.initials: C
authors.lastname: Cywin
authors.forename: Jonathan
authors.initials: J
authors.lastname: Emeigh
authors.forename: Melissa
authors.initials: M
authors.lastname: Foerst
authors.forename: John
authors.initials: J
authors.lastname: Ginn
authors.forename: Matt
authors.initials: M
authors.lastname: Hrapchak
authors.forename: Eugene
authors.initials: E
authors.lastname: Hickey
authors.forename: Ming-Hong
authors.initials: MH
authors.lastname: Hao
authors.forename: Mohammed
authors.initials: M
authors.lastname: Kashem
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Weimin
authors.initials: W
authors.lastname: Liu
authors.forename: Tina
authors.initials: T
authors.lastname: Morwick
authors.forename: Richard
authors.initials: R
authors.lastname: Nelson
authors.forename: Daniel
authors.initials: D
authors.lastname: Marshall
authors.forename: Leslie
authors.initials: L
authors.lastname: Martin
authors.forename: Peter
authors.initials: P
authors.lastname: Nemoto
authors.forename: Ian
authors.initials: I
authors.lastname: Potocki
authors.forename: Michel
authors.initials: M
authors.lastname: Liuzzi
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Peet
authors.forename: Erika
authors.initials: E
authors.lastname: Scouten
authors.forename: David
authors.initials: D
authors.lastname: Stefany
authors.forename: Michael
authors.initials: M
authors.lastname: Turner
authors.forename: Steve
authors.initials: S
authors.lastname: Weldon
authors.forename: Clare
authors.initials: C
authors.lastname: Zimmitti
authors.forename: Denise
authors.initials: D
authors.lastname: Spero
authors.forename: Terence A
authors.initials: TA
authors.lastname: Kelly
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C446540:thienopyridine; D051550:I-kappa B Kinase