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 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.
Shimizu
Hiroki
H
R&D Division, Daiichi Sankyo Co., Ltd, Edogawa-ku, Tokyo, Japan. shimizu.hiroki.hu@daiichisankyo.co.jp
Tanaka
Shinji
S
Toki
Tadashi
T
Yasumatsu
Isao
I
Akimoto
Toshihiko
T
Morishita
Kaoru
K
Yamasaki
Tomonori
T
Yasukochi
Takanori
T
Iimura
Shin
S
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
D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D051550:I-kappa B Kinase