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

Abstract

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.

DOI: 10.1021/jm501867s
020406020162017
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@article{Papakyriakou201534diaminobenzoicAD, title={3,4-diaminobenzoic acid derivatives as inhibitors of the oxytocinase subfamily of M1 aminopeptidases with immune-regulating properties.}, author={Athanasios Papakyriakou and Efthalia Zervoudi and Sofia Tsoukalidou and François-Xavier Mauvais and Georgia Sfyroera and Dimitrios C Mastellos and Peter van Endert and Emmanuel A. Theodorakis and Dionisios Vourloumis and Efstratios Stratikos}, journal={Journal of medicinal chemistry}, year={2015}, volume={58 3}, pages={1524-43} }