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

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 24; pp. 7686 - 7698
• Main Authors: Matsumoto, Shigemitsu, Miyamoto, Naoki, Hirayama, Takaharu, Oki, Hideyuki, Okada, Kengo, Tawada, Michiko, Iwata, Hidehisa, Nakamura, Kazuhide, Yamasaki, Seiji, Miki, Hiroshi, Hori, Akira, Imamura, Shinichi
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2013; Elsevier
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Biochemistry & Molecular Biology; c-Met; Cell Line; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; enzyme activity; Female; Heterocyclic Compounds, 2-Ring - chemistry; Heterocyclic Compounds, 2-Ring - metabolism; Heterocyclic Compounds, 2-Ring - pharmacology; human umbilical vein endothelial cells; Humans; hydrogen bonding; Imidazo[1,2-a]pyridine; Imidazo[1,2-b]pyridazine; Life Sciences & Biomedicine; Mice; Mice, Inbred BALB C; Microsomes, Liver - chemistry; Microsomes, Liver - metabolism; Models, Molecular; Molecular Structure; neoplasms; Niacinamide - analogs & derivatives; Niacinamide - chemistry; Niacinamide - metabolism; Niacinamide - pharmacology; Pharmacology & Pharmacy; Physical Sciences; 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; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacology; Pyridone; Science & Technology; Solubility; Structure-Activity Relationship; vascular endothelial growth factor receptor-2; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR2; VEGFR2; c-Met; WXOGYBWIHWKUMA-UHFFFAOYSA-N; Imidazo[1,2-b]pyridazine; Pyridone; Imidazo[1,2-a]pyridine; METASTASIS; TUMOR ANGIOGENESIS; SORAFENIB; FACTOR RECEPTOR; CANCER; RENAL-CELL CARCINOMA; DISCOVERY; POTENT; EXPRESSION; ENDOTHELIAL GROWTH-FACTOR
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2013.10.028

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, 2.2nM), as well as proliferation of c-Met-addicted MKN45 cells and VEGF-stimulated human umbilical vein endothelial cells (IC50=5.0, 1.8nM). 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, 15mg/kg, once-daily) mouse xenograft models.