Discovery of N-substituted-3-phenyl-1,6-naphthyridinone derivatives bearing quinoline moiety as selective type II c-Met kinase inhibitors against VEGFR-2 |
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| Institution: | 1. Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States;2. Cardiovascular and Metabolic Diseases, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States;3. PK Sciences, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, United States;1. Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan;2. Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan;3. School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, Egypt;3. Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt;4. Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt;1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China;2. College of Pharmacy of Liaoning University, Key Laboratory of New Drug Research and Development of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China |
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| Abstract: | New N-substituted-3-phenyl-1,6-naphthyridinone derivatives are designed and synthesized, based on structural modification of our previously reported compound 3. Extensive enzyme-based SAR studies and PK evaluation led to the discovery of compound 4r, with comparable c-Met potency to that of Cabozantinib and high VEGFR-2 selectivity, while Cabozantinib displayed no VEGFR-2 selectivity. More importantly, at oral doses of 45 mg/kg (Q.D.), compound 4r exhibits significant tumor growth inhibition (93%) in a U-87MG human gliobastoma xenograft model. The promising selectivity against VEGFR-2 and excellent tumor growth inhibition of compound 4r suggest that it could be used as a new lead molecule for further discovery of selective type II c-Met inhibitors. |
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| Keywords: | c-Met kinase inhibitor 1 6-Naphthyridone VEGFR-2 selectivity Antitumor efficacy |
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