Discovery of imidazo[1,2-b]pyridazine derivatives as IKKbeta inhibitors. Part 1: Hit-to-lead study and structure-activity relationship

Imidazo[1,2-b]pyridazine derivatives from high-throughput screening were developed as IKKbeta inhibitors. By the optimization of the 3- and 6-position of imidazo[1,2-b]pyridazine scaffold, cell-free IKKbeta inhibitory activity and TNFalpha inhibitory activity in THP-1 cell increased. Also, these com...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-09, Vol.20 (17), p.5113-5118
Main Authors: Shimizu, Hiroki, Tanaka, Shinji, Toki, Tadashi, Yasumatsu, Isao, Akimoto, Toshihiko, Morishita, Kaoru, Yamasaki, Tomonori, Yasukochi, Takanori, Iimura, Shin
Format: Article
Language:English
Subjects:
Drug Discovery
I-kappa B Kinase - antagonists & inhibitors
Imidazoles - chemistry
Imidazoles - pharmacology
Models, Molecular
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Pyridazines - chemistry
Pyridazines - pharmacology
Structure-Activity Relationship
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Summary:Imidazo[1,2-b]pyridazine derivatives from high-throughput screening were developed as IKKbeta inhibitors. By the optimization of the 3- and 6-position of imidazo[1,2-b]pyridazine scaffold, cell-free IKKbeta inhibitory activity and TNFalpha inhibitory activity in THP-1 cell increased. Also, these compounds showed high kinase selectivity. The structure-activity relationship was revealed and the interaction model of imidazo[1,2-b]pyridazine compounds with IKKbeta was constructed.
ISSN:1464-3405
DOI:10.1016/j.bmcl.2010.07.026