1. The discovery of thienopyridine analogues as potent IκB kinase β inhibitors. Part II
- Author
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Richard M. Nelson, Emeigh Jonathan Emilian, Terence A. Kelly, Gregory W. Peet, Eugene R. Hickey, Jiang-Ping Wu, Jun Li, Clare Zimmitti, Janice R. Brickwood, John D. Ginn, Charles L. Cywin, Melissa Foerst, David Stefany, Erika Scouten, Roman Wolfgang Fleck, Zhidong Chen, Mohammed A. Kashem, Daniel Richard Marshall, Steve M. Weldon, Ming-Hong Hao, Weimin Liu, Matt Hrapchak, Catron Katrina Mary, Ian Potocki, Tina Morwick, Peter Allen Nemoto, Michel Liuzzi, Leslie Martin, Denise Spero, Alison Capolino, and Michael Robert Turner
- Subjects
Lipopolysaccharides ,Thienopyridine ,Pyridines ,Stereochemistry ,Clinical Biochemistry ,Pharmaceutical Science ,IκB kinase ,Biochemistry ,Mice ,Structure-Activity Relationship ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Protein Kinase Inhibitors ,Molecular Biology ,Reporter gene ,biology ,Tumor Necrosis Factor-alpha ,Kinase ,Drug discovery ,Chemistry ,Organic Chemistry ,NF-kappa B ,I-kappa B Kinase ,Enzyme inhibitor ,biology.protein ,Molecular Medicine ,Signal transduction ,HeLa Cells ,Signal Transduction - 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.
- Published
- 2009
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