title: Design, synthesis, and evaluation of imidazo[1,2-b]pyridazine derivatives having a benzamide unit as novel VEGFR2 kinase inhibitors.
abstract: The vascular endothelial growth factor (VEGF) signaling pathway has been implicated in tumor angiogenesis, and inhibition of the VEGF pathway is considered an efficacious method for treating cancer. Herein, we describe synthetic studies of imidazo[1,2-b]pyridazine derivatives as VEGF receptor 2 (VEGFR2) kinase inhibitors. The imidazo[1,2-b]pyridazine scaffold was designed and synthesized as a hinge binder according to the previously reported crystal structure of pyrrolo[3,2-d]pyrimidine 1 with VEGFR2. Structure-activity relationship studies revealed that meta-substituted 6-phenoxy-imidazo[1,2-b]pyridazine derivatives had potent affinity for VEGFR2. In particular, N-[3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-3-(trifluoromethyl)benzamide (6b) exhibited strong inhibitory activity against VEGFR2 with an IC(50) value of 7.1 nM, and it inhibited platelet-derived growth factor receptor β kinase with an IC(50) value of 15 nM.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1, Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Yuya
authors.initials: Y
authors.lastname: Oguro
authors.forename: Terufumi
authors.initials: T
authors.lastname: Takagi
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Iwata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Akira
authors.initials: A
authors.lastname: Hori
authors.forename: Shinichi
authors.initials: S
authors.lastname: Imamura
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011471:Prostatic Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; C037689:benzamide; D040301:Vascular Endothelial Growth Factor Receptor-2