Discovery of potent and orally active tricyclic-based FBPase inhibitors

Bioorg Med Chem. 2010 Jul 15;18(14):5346-51. doi: 10.1016/j.bmc.2010.05.041. Epub 2010 May 20.

Abstract

With the aim of exploring the effect of tricyclic-based FBPase inhibitors in cells and in vivo, a series of prodrugs of tricyclic phosphonates was designed and synthesized. Introducing prodrug moieties into tricyclic-based phosphonates led to the discovery of prodrug 15c, which strongly inhibited glucose production in monkey hepatocytes. Furthermore, prodrug 15c lowered blood glucose levels in fasted cynomolgus monkeys.

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Glucose / metabolism
  • Cells, Cultured
  • Crystallography, X-Ray
  • Diabetes Mellitus, Type 2 / drug therapy
  • Drug Design
  • Fructose-Bisphosphatase / antagonists & inhibitors*
  • Fructose-Bisphosphatase / chemistry
  • Fructose-Bisphosphatase / metabolism*
  • Glucose / antagonists & inhibitors*
  • Hepatocytes / metabolism
  • Humans
  • Macaca fascicularis
  • Models, Molecular
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / pharmacology*

Substances

  • Blood Glucose
  • Organophosphonates
  • Prodrugs
  • Fructose-Bisphosphatase
  • Glucose