TIE-2/VEGF-R2 SAR and in vitro activity of C3-acyl dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs

Bioorg Med Chem Lett. 2008 Apr 1;18(7):2368-72. doi: 10.1016/j.bmcl.2008.02.069. Epub 2008 Mar 4.

Abstract

Orally bioavailable, dual inhibitors of TIE-2/VEGF-R2 were identified by elaborating the C3/N13 SAR around a fused pyrrolodihydroindazolocarbazole scaffold. Analogs bearing a C3-thiophencarbonyl group were evaluated in enzymatic and cellular biochemical assays; two orally bioavailable analogs were further profiled in functional assays and found to inhibit microvessel growth in rat aortic explant cultures and inhibit Ang-1-stimulated chemotaxis of HUVECs.

MeSH terms

  • Acylation
  • Angiogenesis Inhibitors / chemical synthesis
  • Angiogenesis Inhibitors / pharmacokinetics*
  • Angiotensin I
  • Animals
  • Aorta / cytology
  • Aorta / drug effects*
  • Aorta / metabolism
  • Biological Availability
  • Cells, Cultured
  • Chemotaxis / physiology
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacokinetics*
  • Indazoles / chemical synthesis
  • Indazoles / pharmacology*
  • Indoles / chemical synthesis
  • Indoles / pharmacology*
  • Models, Chemical
  • Rats
  • Receptor, TIE-2 / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Thiophenes / chemistry
  • Umbilical Veins / cytology
  • Umbilical Veins / drug effects*
  • Umbilical Veins / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

  • Angiogenesis Inhibitors
  • Enzyme Inhibitors
  • Indazoles
  • Indoles
  • Thiophenes
  • Angiotensin I
  • Receptor, TIE-2
  • Vascular Endothelial Growth Factor Receptor-2