Pyrimidinylacetamide-based 2-pyridylureas as Angiogenesis Inhibitors: Design, Synthesis and Biological Evaluation.

ABSTRACT

BACKGROUND: VEGFR-2 inhibitors have been widely used in the treatment of cancer. In our continued efforts to search for potent and novel VEGFR-2 inhibitors as antitumor agents, we have identified a series of ureas and amides bearing a oxazolopyrimidine scaffold. AIM OF THE STUDY To discover more potent VEGFR-2 inhibitors with stronger binding affinity and better physical and chemical properties. METHODS: 23 pyrimidinylacetamide-based ureas were designed and synthesized. Replacement of oxazolopyrimidine with a pyrimidinylacetamide generated a series of novel VEGFR-2 inhibitors. RESULTS AND CONCLUSIONS: In HUVEC inhibition assay, the most potent compound (compound 16) possessed an IC50 value of 0.43 µM. Compound 16 also inhibited the migration and capillary like tube formation of HUVECs with inhibition rate at 22% (1 µM) and 17.5% (0.8 µM) respectively. These results support the further investigation of compound 16 as a potential anti-cancer agent.