2. Academic Validation
  3. Discovery of biphenyl-aryl ureas as novel VEGFR-2 inhibitors. Part 4: exploration of diverse hinge-binding fragments

Discovery of biphenyl-aryl ureas as novel VEGFR-2 inhibitors. Part 4: exploration of diverse hinge-binding fragments

  • Bioorg Med Chem. 2015 Jul 1;23(13):3228-36. doi: 10.1016/j.bmc.2015.04.071.
Ping Su 1,  Jinfeng Wang 1,  Yaling Shi 1,  Xiaoyan Pan 1,  Ruili Shao 1,  Jie Zhang 2
Affiliations

Affiliations

  • 1 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China.
  • 2 School of Pharmacy, Health Science Center, Xi'an Jiaotong University, No. 76, Yanta West Road, Xi'an, Shaanxi Province 710061, PR China. Electronic address: zhj8623@mail.xjtu.edu.cn.
PMID: 25982075 DOI: 10.1016/j.bmc.2015.04.071
Abstract

VEGFR-2 plays an essential role in angiogenesis and is an important target for Cancer therapy. A series of biphenyl-aryl ureas were synthesized and evaluated as novel VEGFR-2 inhibitors. The pyridine, methylamine carbonyl pyridine and pivaloyl amide pyridine were introduced as novel hinge binding fragment. The majority of title compounds displayed potent VEGFR-2 inhibition. In particular, L1, L9, W14 and W15 exhibited significant enzymatic inhibitory activity with IC50 values of 0.36nM, 0.22nM, 0.15nM and 0.14nM. Compounds L1, L9 and W15 displayed potent antiproliferative activity against A549 and SMMC-7721 cells. SAR study suggested that incorporation of 3-trifluoromethyl and methylamine carbonyl on terminal pyridine could improve VEGFR-2 inhibitory activity. Molecular docking illustrated that urea moiety formed two critical hydrogen bonds with the DFG residues of VEGFR-2. The results indicated that these biphenyl-aryl ureas could serve as promising lead compounds for further optimization.

Keywords

Biphenyl; Hinge region; Structural diversity; Urea; VEGFR-2 inhibitors.

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