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

Shigemitsu Matsumoto; Naoki Miyamoto; Takaharu Hirayama; Hideyuki Oki; Kengo Okada; Michiko Tawada; Hidehisa Iwata; Kazuhide Nakamura; Seiji Yamasaki; Hiroshi Miki; Akira Hori; Shinichi Imamura

doi:10.1016/j.bmc.2013.10.028

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

Bioorg Med Chem. 2013 Dec 15;21(24):7686-98. doi: 10.1016/j.bmc.2013.10.028. Epub 2013 Oct 30.

Authors

Shigemitsu Matsumoto¹, Naoki Miyamoto, Takaharu Hirayama, Hideyuki Oki, Kengo Okada, Michiko Tawada, Hidehisa Iwata, Kazuhide Nakamura, Seiji Yamasaki, Hiroshi Miki, Akira Hori, Shinichi Imamura

Affiliation

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 2-26-1, Muraokahigashi, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: [email protected].

PMID: 24216091
DOI: 10.1016/j.bmc.2013.10.028

Abstract

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.

Keywords: Imidazo[1,2-a]pyridine; Imidazo[1,2-b]pyridazine; Pyridone; VEGFR2; WXOGYBWIHWKUMA-UHFFFAOYSA-N; c-Met.

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Cell Line
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Female
Heterocyclic Compounds, 2-Ring / chemistry
Heterocyclic Compounds, 2-Ring / metabolism
Heterocyclic Compounds, 2-Ring / pharmacology*
Humans
Mice
Mice, Inbred BALB C
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Models, Molecular
Molecular Structure
Niacinamide / analogs & derivatives*
Niacinamide / chemistry
Niacinamide / metabolism
Niacinamide / pharmacology
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Pyridines / chemistry
Pyridines / metabolism
Pyridines / pharmacology*
Solubility
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Heterocyclic Compounds, 2-Ring
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
Protein Kinase Inhibitors
Pyridines
Niacinamide
Proto-Oncogene Proteins c-met
Vascular Endothelial Growth Factor Receptor-2
imidazo(1,2-a)pyridine