Design,synthesis and biological evaluation of 1H-pyrrolo[2,3-b]pyridine and 1H-pyrazolo[3,4-b]pyridine derivatives as c-Met inhibitors |
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| Affiliation: | 1. School of Biological Engineering, Tianjin University of Science and Technology, #29, 13th Avenue, TEDA, Tianjin 300457, China;2. Tianjin Binjiang Pharma, Inc., #238 Baidi Road, Nankai District, Tianjin 300192, China;3. Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, #238 Baidi Road, Nankai District, Tianjin 300192, China;1. Departamento de Química Orgánica and UMYMFOR (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Ciudad de Buenos Aires, Argentina;2. Departamento de Química Biológica and IFIBYNE (CONICET-UBA), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Pabellón 2, Ciudad Universitaria, C1428EGA Ciudad de Buenos Aires, Argentina;1. Medicinal Chemistry, Fibrosis and Lung Injury DPU, Respiratory Therapeutic Area, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom;2. Platform Technology & Science, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom;3. Global Spectroscopy, Structural and Metabolite ID, Platform Technology and Science, GlaxoSmithKline, 709, Swedeland Road, King of Prussia, PA 19087, United States;4. Platform Technology and Science, GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, United States;1. Department of Chemistry, University of Lucknow, Lucknow 226007, Uttar Pradesh, India;2. ‘Hygeia’, Center of Excellences in Pharmaceutical Sciences (CEPS), Guru Govind Singh Indraprastha University, Sec 16-C, Dwarka, New Delhi 110078, India;1. Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, LT-50254 Kaunas, Lithuania;2. Institute of Synthetic Chemistry, Kaunas University of Technology, K. Baršausko g. 59, LT-51423 Kaunas, Lithuania;1. University of Utah, Department of Chemistry, Salt Lake City, UT 84112, USA;2. Laboratory of Cancer Biology and Genetics, NCI, National Institutes of Health, Bethesda, MD 20892-4255, USA |
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| Abstract: | Five novel 1H-pyrrolo[2,3-b]pyridine or 1H-pyrazolo[3,4-b]pyridine derivatives, with a methylene, sulfur, sulfoxide or cyclopropyl group as a linker, were designed, synthesized and biologically evaluated against c-Met and ALK. The development of these methods of compound synthesis may provide an important reference for the construction of novel 7-azaindole and 7-azaindazole derivatives with a single atom linker. The enzyme assay and cell assay in vitro showed that compound 9 displayed strong c-Met kinase inhibition with IC50 of 22.8 nM, moderate ALK kinase inhibition, and strong cell inhibition with MKN-45 IC50 of 329 nM and EBC-1 IC50 of 479 nM. In order to find the better candidate compounds, compounds 8, 9 and 10 have been selected as tool compounds for further optimization. |
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| Keywords: | c-Met inhibitor Azaindole Azaindazole Synthesis Biological evaluation |
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