The discovery of thienopyridine analogues as potent IkappaB kinase beta inhibitors. Part II.
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.
Wu
Jiang-Ping
JP
Research and Development, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Road, Ridgefield, CT 06877, United States. jiang_ping.wu@boehringer-ingelheim.com
Fleck
Roman
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Brickwood
Janice
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Capolino
Alison
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Catron
Katrina
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Chen
Zhidong
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Cywin
Charles
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Emeigh
Jonathan
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Foerst
Melissa
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Ginn
John
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Hrapchak
Matt
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Hickey
Eugene
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Hao
Ming-Hong
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Kashem
Mohammed
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Li
Jun
J
Liu
Weimin
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Morwick
Tina
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Nelson
Richard
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Marshall
Daniel
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Martin
Leslie
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Nemoto
Peter
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Potocki
Ian
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Liuzzi
Michel
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Peet
Gregory W
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Scouten
Erika
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Stefany
David
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Turner
Michael
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Weldon
Steve
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Clare
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Spero
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Terence A
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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
D008070:Lipopolysaccharides; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; C446540:thienopyridine; D051550:I-kappa B Kinase