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

Add time:07/20/2019    Source:sciencedirect.com

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 0.36 nM, 0.22 nM, 0.15 nM and 0.14 nM. 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.

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