Novel benzimidazole derivatives selectively inhibit endothelial cell growth and suppress angiogenesis in vitro and in vivo.
We discovered a novel benzimidazole derivative, named compound (comp.) 1, with unique antiangiogenic characteristics. Comp.1 cytostatically inhibited the vascular endothelial growth factor- and basic fibroblast growth factor-induced growth of endothelial cells (50% inhibitory concentration: 29-79 nM) without a cytotoxic phase, but did not affect the growth of other types of cells up to 90 microM. Comp.1 also inhibited the tube formation derived from a rat aorta fragment, but the oral (p.o.) treatment of comp.1 (46 mg/kg, administered twice daily (b.i.d.)) did not inhibit aniogenesis in a mouse sponge model. Comp.8, an analogue of comp.1, showed a specific inhibitory effect on endothelial cell growth. Comp.8 also suppressed angiogenesis (15 mg/kg, b.i.d., p.o., 70% inhibition) in the sponge model without body weight loss.
Hori
Akira
A
Pharmaceutical Discovery Research Division, Takeda Chemical Industries, Ltd., Jusohonmachi, 2-17-85 Yodogawa-ku, 532-8686, Osaka, Japan. hori_akira@takeda.co.jp
Imaeda
Yasuhiro
Y
Kubo
Keiji
K
Kusaka
Masami
M
D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008222:Lymphokines / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009924:Organ Culture Techniques; D051381:Rats; D013329:Structure-Activity Relationship; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014680:Veins / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects
D001562:Benzimidazoles; D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors