title: Discovery of imidazo[1,2-b]pyridazine derivatives as IKKbeta inhibitors. Part 1: Hit-to-lead study and structure-activity relationship.
abstract: 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.
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: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.forename: Tadashi
authors.initials: T
authors.lastname: Toki
authors.forename: Isao
authors.initials: I
authors.lastname: Yasumatsu
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Akimoto
authors.forename: Kaoru
authors.initials: K
authors.lastname: Morishita
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Takanori
authors.initials: T
authors.lastname: Yasukochi
authors.forename: Shin
authors.initials: S
authors.lastname: Iimura
mesh_terms: D055808:Drug Discovery; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D051550:I-kappa B Kinase