Novel C-3 N-urea, amide, and carbamate dihydroindazolo[5,4-a]pyrrolo[3,4-c]carbazole analogs as potent TIE-2 and VEGF-R2 dual inhibitors

Bioorg Med Chem Lett. 2006 Oct 15;16(20):5368-72. doi: 10.1016/j.bmcl.2006.07.066. Epub 2006 Aug 4.

Abstract

A novel series of C-3 urea, amide, and carbamate fused dihydroindazolocarbazole (DHI) analogs are reported as highly potent dual inhibitors of TIE-2 and VEGF-R2 receptor tyrosine kinases with excellent cellular potency. Structure-activity relationship (SAR) studies indicate the optimal N-13 alkyl substitutions are n-propyl and i-butyl. The isopropyl carbamate 39 displayed good dual enzyme, cell potency, and rat pharmacokinetic properties for advancement to in vivo evaluation.

MeSH terms

  • Administration, Oral
  • Amides / chemistry*
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Biological Availability
  • Carbamates / chemistry*
  • Carbazoles / chemical synthesis
  • Carbazoles / chemistry
  • Carbazoles / pharmacology*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Indazoles / chemical synthesis
  • Indazoles / chemistry
  • Indazoles / pharmacology*
  • Mice
  • Mice, Nude
  • Molecular Structure
  • Rats
  • Receptor, TIE-2 / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Urea / chemistry*
  • Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

  • Amides
  • Antineoplastic Agents
  • Carbamates
  • Carbazoles
  • Enzyme Inhibitors
  • Indazoles
  • Urea
  • Receptor, TIE-2
  • Vascular Endothelial Growth Factor Receptor-2