title: Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 2: improvement of potency in vitro and in vivo.
abstract: We have increased the potency of imidazo[1,2-b]pyridazine derivatives as IKKβ inhibitors with two strategies. One is to enhance the activity in cell-based assay by adjusting the polarity of molecules to improve permeability. Another is to increase the affinity for IKKβ by the introduction of additional substituents based on the hypothesis derived from an interaction model study. These improved compounds showed inhibitory activity of TNFα production in mice.
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd, Edogawa-ku, Tokyo, Japan. shimizu.hiroki.hu@daiichisankyo.co.jp
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Isao
authors.initials: I
authors.lastname: Yasumatsu
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hamada
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yoneda
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Tadashi
authors.initials: T
authors.lastname: Toki
authors.forename: Mika
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Kaoru
authors.initials: K
authors.lastname: Morishita
authors.forename: Shin
authors.initials: S
authors.lastname: Iimura
mesh_terms: D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008297:Male; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase