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

Ya-Hui Deng; Zhong-Hui Yan; Ji-Ping Liu; Yu Liu; Li-Ping Sun

doi:10.1016/j.arcmed.2017.08.004

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

Arch Med Res. 2017 May;48(4):333-342. doi: 10.1016/j.arcmed.2017.08.004. Epub 2017 Sep 4.

Authors

Ya-Hui Deng¹, Zhong-Hui Yan², Ji-Ping Liu², Yu Liu², Li-Ping Sun³

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China; Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
² School of Life Science and Technology, China Pharmaceutical University, Nanjing, P. R. China.
³ Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, P. R. China. Electronic address: chslp@cpu.edu.cn.

PMID: 28882321
DOI: 10.1016/j.arcmed.2017.08.004

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.

Keywords: Anti-angiogenesis; Anti-proliferative activity; Pyrimidinylacetamide; Ureas; VEGFR-2.

MeSH terms

Acetamides / chemical synthesis
Acetamides / chemistry*
Acetamides / pharmacology
Angiogenesis Inhibitors / chemical synthesis
Angiogenesis Inhibitors / chemistry*
Angiogenesis Inhibitors / pharmacology
Cell Proliferation / drug effects
Human Umbilical Vein Endothelial Cells
Humans
Phenylurea Compounds / chemical synthesis
Phenylurea Compounds / chemistry*
Phenylurea Compounds / pharmacology
Pyridines / chemical synthesis
Pyridines / chemistry*
Pyridines / pharmacology
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology
Structure-Activity Relationship
Urea / analogs & derivatives*
Urea / chemical synthesis
Urea / chemistry*
Urea / pharmacology
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors

Substances

Acetamides
Angiogenesis Inhibitors
N-(6-((6-(3-(4-chlorophenyl)ureido)pyridin-3-yl)amino)-2-methylpyrimidin-4-yl)acetamide
Phenylurea Compounds
Pyridines
Pyrimidines
Urea
Vascular Endothelial Growth Factor Receptor-2