title: Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 3: exploration of effective compounds in arthritis models.
abstract: We have discovered imidazo[1,2-b]pyridazine derivatives that show suppressive activity of inflammation in arthritis models. We optimized the substructures of imidazo[1,2-b]pyridazine derivatives to combine potent IKKβ inhibitory activity, TNFα inhibitory activity in vivo and excellent pharmacokinetics. The compound we have acquired, which had both potent activities and good pharmacokinetic profiles based on improved physicochemical properties, demonstrated efficacy on collagen-induced arthritis models in mice and rats.
authors.affiliation: R&D Division, Daiichi Sankyo Co, Ltd, Tokyo, Japan. shimizu.hiroki.hu@daiichisankyo.co.jp
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shimizu
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yoneda
authors.forename: Fumihito
authors.initials: F
authors.lastname: Muro
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Hamada
authors.forename: Takanori
authors.initials: T
authors.lastname: Yasukochi
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: D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry*; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D011724:Pyridazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014409:Tumor Necrosis Factor-alpha; C029899:imidazole; D051550:I-kappa B Kinase