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Novel 2,3-Dihydro-1,4-Benzoxazines as Potent and Orally Bioavailable Inhibitors of Tumor-Driven Angiogenesis
- Source :
- Journal of Medicinal Chemistry. 51:1695-1705
- Publication Year :
- 2008
- Publisher :
- American Chemical Society (ACS), 2008.
-
Abstract
- Angiogenesis is vital for solid tumor growth, and its prevention is a proven strategy for the treatment of disease states such as cancer. The vascular endothelial growth factor (VEGF) pathway provides several opportunities by which small molecules can act as inhibitors of endothelial proliferation and migration. Critical to these processes is signaling through VEGFR-2 or the kinase insert domain receptor (KDR) upon stimulation by its ligand VEGF. Herein, we report the discovery of 2,3-dihydro-1,4-benzoxazines as inhibitors of intrinsic KDR activity (IC 50 < 0.1 microM) and human umbilical vein endothelial cell (HUVEC) proliferation with IC 50 < 0.1 microM. More specifically, compound 16 was identified as a potent (KDR: < 1 nM and HUVEC: 4 nM) and selective inhibitor that exhibited efficacy in angiogenic in vivo models. In addition, this series of molecules is typically well-absorbed orally, further demonstrating the 2,3-dihydro-1,4-benzoxazine moiety as a promising platform for generating kinase-based antiangiogenic therapeutic agents.
- Subjects :
- Male
Models, Molecular
Vascular Endothelial Growth Factor A
Angiogenesis
Injections, Subcutaneous
Administration, Oral
Biological Availability
Mice, Nude
Angiogenesis Inhibitors
Crystallography, X-Ray
Ligands
Cell Line
Rats, Sprague-Dawley
Mice
Structure-Activity Relationship
chemistry.chemical_compound
Growth factor receptor
Neoplasms
Drug Discovery
Animals
Humans
Corneal Neovascularization
Cell Proliferation
Mice, Inbred BALB C
Dose-Response Relationship, Drug
Molecular Structure
Neovascularization, Pathologic
Chemistry
Endothelial Cells
Stereoisomerism
Kinase insert domain receptor
Vascular Endothelial Growth Factor Receptor-2
Benzoxazines
Rats
Endothelial stem cell
Vascular endothelial growth factor
Vascular endothelial growth factor A
Biochemistry
Models, Animal
cardiovascular system
Cancer research
Molecular Medicine
Female
Human umbilical vein endothelial cell
Signal transduction
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 51
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....64dafc54f7435bfc86e716abcc843b0d