The indazole derivative YD-3 specifically inhibits thrombin-induced angiogenesis in vitro and in vivo.
Angiogenesis is a process that involves endothelial cell proliferation, migration, invasion, and tube formation, and the inhibition of these processes has implications for angiogenesis-mediated disorders. The purpose of this study was to examine the antiangiogenic efficacy of YD-3 [1-benzyl-3(ethoxycarbonylphenyl)-indazole], a selective thrombin inhibitor, on thrombin-induced endothelial cell proliferation and neoangiogenesis in a murine Matrigel model. First, the effect of YD-3 on angiogenesis was evaluated in vivo using the mouse Matrigel implant model. Plugs treated with 1 and 10 μM of YD-3 inhibited neovascularization induced by thrombin, protease-activated receptor (PAR) 1, and PAR-4, but not by vascular endothelial growth factor, in a concentration-dependent manner over 7 days. These results indicate that YD-3 has specific antiangiogenic activity on thrombin. YD-3 also inhibited (in a concentration-dependent manner) the ability of thrombin, PAR-1, and PAR-4, but not PAR-2, to induce the proliferation of human umbilical vascular endothelial cells, using a [³H]thymidine incorporation assay. YD-3 predominantly inhibited thrombin-induced vascular endothelial growth factor receptor 2 (Flk-1) expression, but not extracellular signal-regulated kinase 1/2 phosphorylation, using Western blot analysis. YD-3 may have benefit in elucidating pathophysiology induced by thrombin-induced angiogenesis.
Peng
Chieh-Yu
CY
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
Pan
Shiow-Lin
SL
Pai
Hui-Chen
HC
Tsai
An-Chi
AC
Guh
Jih-Hwa
JH
Chang
Ya-Ling
YL
Kuo
Sheng-Chu
SC
Lee
Fang-Yu
FY
Teng
Che-Ming
CM
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007191:Indazoles / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C412964:1-benzyl-3-(ethoxycarbonylpheny)-indazole; D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D007191:Indazoles; D040301:Vascular Endothelial Growth Factor Receptor-2; D013917:Thrombin