Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 18, Issue 20, Pages 7150-7163Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2010.08.042
Keywords
VEGFR; FGFR; Pyrrolo[3,2-d] pyrimidine; Urea
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We have recently reported the discovery of pyrrolo[3,2-d] pyrimidine derivatives 1a and 1b as potent triple inhibitors of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and Tie-2 kinases. To identify compounds having strong inhibitory activity against fibroblast growth factor receptor (FGFR) kinase, further modification was conducted using the co-crystal structure analysis of VEGFR2 and 1b. Among the compounds synthesized, urea derivative 11l having a piperazine moiety on the terminal benzene ring showed strong inhibitory activity against FGFR1 kinase as well as VEGFR2 kinase. A binding model of 11l complexed with VEGFR2 suggested that the piperazine moiety forms additional interactions with Ile1025 and His1026. (C) 2010 Elsevier Ltd. All rights reserved.
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