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.