Synthesis of (3-(2-Aminopyrimidin-4-yl)-4-hydroxyphenyl)phenyl Methanone Analogues as Inhibitors of Vascular Endothelial Growth Factor Receptor-2 Kinase

摘要

Angiogenesis is critical for tumor growth and mediated mainly by vascular endothelial growth factor (VEGF) signaling. Inhibition of the VEGF signaling pathway has emerged as one of the promising approaches for cancer therapy. VEGF receptor 2 (VEGFR-2) is considered as a major mediator of angiogenic effects of VEGF. We describe herein the discovery of a series of potent VEGFR-2 tyrosine kinase (KDR) inhibitors from a new 2-(2-aminopyrimidin-4-yl)phenol scaffold. The KDR activity was reduced appreciably by a series of compounds with a benzoyl group at position 4 of phenol ring. The structure-activity relationships for a series of (3-(2-aminopyrimidin-4-yl)-4-hydroxyphenyl)phenyl methanones revealed compound 9 (KDR IC50 = 25 nM) as the most potent inhibitor in the series. Compound 22 had a potent cellular activity on VEGF-induced HUVEC cell growth (IC50 < 0.1 mu M) with high selectivity over HCT116.