3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of M1 aminopeptidases with immune-regulating properties

J Med Chem. 2015 Feb 12;58(3):1524-43. doi: 10.1021/jm501867s. Epub 2015 Jan 30.


Members of the oxytocinase subfamily of M1 aminopeptidases (ERAP1, ERAP2, and IRAP) play important roles in both the adaptive and innate human immune responses. Their enzymatic activity can contribute to the pathogenesis of several major human diseases ranging from viral and parasitic infections to autoimmunity and cancer. We have previously demonstrated that diaminobenzoic acid derivatives show promise as selective inhibitors for this group of aminopeptidases. In this study, we have thoroughly explored a series of 3,4-diaminobenzoic acid derivatives as inhibitors of this class of enzymes, achieving submicromolar inhibitors for ERAP2 (IC50 = 237 nM) and IRAP (IC50 = 105 nM). Cell-based analysis indicated that the lead compounds can be effective in downregulating macrophage activation induced by lipopolysaccharide and interferon-γ as well as cross-presentation by bone marrow-derived dendritic cells. Our results indicate that this class of inhibitors may be useful for the targeted downregulation of immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminobenzoates / chemical synthesis
  • Aminobenzoates / chemistry
  • Aminobenzoates / pharmacology*
  • Aminopeptidases / antagonists & inhibitors*
  • Aminopeptidases / immunology*
  • Aminopeptidases / metabolism
  • Animals
  • Cell Line
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship


  • Aminobenzoates
  • Enzyme Inhibitors
  • 3,4-diaminobenzoic acid
  • Aminopeptidases