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Discovery of 1,3‐Diaryl‐pyridones as Potent VEGFR ‐2 Inhibitors: Design, Synthesis, and Biological Evaluation
Author(s) -
Yan Wei,
Huang Zhaoru,
Wang Zhengyu,
Cao Sufen,
Tong Linjiang,
Zhang Tao,
Wang Chen,
Zhou Lin,
Ding Jian,
Luo Cheng,
Zhou Jinpei,
Xie Hua,
Duan Wenhu
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12703
Subject(s) - vegf receptors , computational biology , chemistry , combinatorial chemistry , drug discovery , biology , biochemistry , cancer research
In this study, we described the design, synthesis, and biological evaluation of 1,3‐diaryl‐pyridones as vascular endothelial growth factor receptor‐2 ( VEGFR ‐2) inhibitors. The 1,3‐diaryl‐pyridones were synthesized via Chan‐Lam and Suzuki coupling reactions. Two representative compounds, 17 and 35h , displayed excellent enzymatic inhibitory activities, with IC 50 values of 3.5 and 3.0 n m , respectively. Furthermore, compounds 17 and 35h blocked the tube formation and suppressed the VEGF ‐induced phosphorylation of VEGFR ‐2 and downstream extracellular signal‐regulated kinases (Erk) in human umbilical vein endothelial cells ( HUVEC s) at 10 n m concentration. The docking simulation showed that compound 17 bound well into the active site of VEGFR ‐2 via two hydrogen bonds and hydrophobic interactions.