Structure-based design, synthesis, and evaluation of imidazo[1,2-b]pyridazine and imidazo[1,2-a]pyridine derivatives as novel dual c-Met and VEGFR2 kinase inhibitors.
To identify compounds with potent antitumor efficacy for various human cancers, we aimed to synthesize compounds that could inhibit c-mesenchymal epithelial transition factor (c-Met) and vascular endothelial growth factor receptor 2 (VEGFR2) kinases. We designed para-substituted inhibitors by using co-crystal structural information from c-Met and VEGFR2 in complex with known inhibitors. This led to the identification of compounds 3a and 3b, which were capable of suppressing both c-Met and VEGFR2 kinase activities. Further optimization resulted in pyrazolone and pyridone derivatives, which could form intramolecular hydrogen bonds to enforce a rigid conformation, thereby producing potent inhibition. One compound of particular note was the imidazo[1,2-a]pyridine derivative (26) bearing a 6-methylpyridone ring, which strongly inhibited both c-Met and VEGFR2 enzyme activities (IC50=1.9, 2.2 nM), as well as proliferation of c-Met-addicted MKN45 cells and VEGF-stimulated human umbilical vein endothelial cells (IC50=5.0, 1.8 nM). Compound 26 exhibited dose-dependent antitumor efficacy in vivo in MKN45 (treated/control ratio [T/C]=4%, po, 5mg/kg, once-daily) and COLO205 (T/C=13%, po, 15 mg/kg, once-daily) mouse xenograft models.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1, Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: shigemitsu.matsumoto@takeda.com.
Shigemitsu
S
Matsumoto
Naoki
N
Miyamoto
Takaharu
T
Hirayama
Hideyuki
H
Oki
Kengo
K
Okada
Michiko
M
Tawada
Hidehisa
H
Iwata
Kazuhide
K
Nakamura
Seiji
S
Yamasaki
Hiroshi
H
Miki
Akira
A
Hori
Shinichi
S
Imamura
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006574:Heterocyclic Compounds, 2-Ring / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012995:Solubility; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000970:Antineoplastic Agents; D006574:Heterocyclic Compounds, 2-Ring; C586449:N-(4-((2-((cyclopropylcarbonyl)amino)imidazo(1,2-a)pyridin-6-yl)oxy)-3-fluorophenyl)-6-methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D009536:Niacinamide; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2; C001439:imidazo(1,2-a)pyridine
Imidazo[1,2-a]pyridine; Imidazo[1,2-b]pyridazine; Pyridone; VEGFR2; WXOGYBWIHWKUMA-UHFFFAOYSA-N; c-Met