title: Discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (TAK-593), a highly potent VEGFR2 kinase inhibitor.
abstract: Vascular endothelial growth factor (VEGF) plays important roles in tumor angiogenesis, and the inhibition of its signaling pathway is considered an effective therapeutic option for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of 2-acylamino-6-phenoxy-imidazo[1,2-b]pyridazine derivatives. Hybridization of two distinct imidazo[1,2-b]pyridazines 1 and 2, followed by optimization led to the discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (23a, TAK-593) as a highly potent VEGF receptor 2 kinase inhibitor with an IC50 value of 0.95 nM. The compound 23a strongly suppressed proliferation of VEGF-stimulated human umbilical vein endothelial cells with an IC50 of 0.30 nM. Kinase selectivity profiling revealed that 23a inhibited platelet-derived growth factor receptor kinases as well as VEGF receptor kinases. Oral administration of 23a at 1 mg/kg bid potently inhibited tumor growth in a mouse xenograft model using human lung adenocarcinoma A549 cells (T/C=8%).
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.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Nozomu
authors.initials: N
authors.lastname: Sakai
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Takaharu
authors.initials: T
authors.lastname: Hirayama
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Miwa
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Oguro
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Oki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Okada
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Terufumi
authors.initials: T
authors.lastname: Takagi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Iwata
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Awazu
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Takeuchi
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Hori
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1 Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: shin-ichi.imamura@takeda.com.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Imamura
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008819:Mice, Nude; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D000620:Aminoimidazole Carboxamide; D040301:Vascular Endothelial Growth Factor Receptor-2