Discovery of potent competitive inhibitors of indoleamine 2,3-dioxygenase with in vivo pharmacodynamic activity and efficacy in a mouse melanoma model

J Med Chem. 2009 Dec 10;52(23):7364-7. doi: 10.1021/jm900518f.

Abstract

A hydroxyamidine chemotype has been discovered as a key pharmacophore in novel inhibitors of indoleamine 2,3-dioxygenase (IDO). Optimization led to the identification of 5l, which is a potent (HeLa IC(50) = 19 nM) competitive inhibitor of IDO. Testing of 5l in mice demonstrated pharmacodynamic inhibition of IDO, as measured by decreased kynurenine levels (>50%) in plasma and dose dependent efficacy in mice bearing GM-CSF-secreting B16 melanoma tumors.

MeSH terms

  • Amidines / chemistry
  • Amidines / metabolism
  • Amidines / pharmacology
  • Amidines / therapeutic use
  • Animals
  • Binding, Competitive*
  • Disease Models, Animal
  • Disease Progression
  • Drug Discovery
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Gene Expression Regulation, Neoplastic / drug effects
  • HeLa Cells
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / chemistry
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Inhibitory Concentration 50
  • Melanoma / drug therapy
  • Melanoma / enzymology*
  • Melanoma / genetics
  • Melanoma / pathology
  • Mice
  • Models, Molecular
  • Molecular Conformation

Substances

  • Amidines
  • Enzyme Inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase