Discovery ofNew Nanomolar Selective IRAP Inhibitors

Among the M1 family of oxytocinase aminopeptidases, insulin-regulated aminopeptidase IRAP, is an emerging drug target implicated in various biological pathways and particularly in MHC-I antigen presentation through amino-terminal trimming of exogenous cross-presented peptides. A few series of inhibitors inspired either by angiotensin IV, one of IRAP substrates, or by bestatin a pan aminopeptidase inhibitor, have been disclosed. However, the variety and number of chemotypes remains relatively limited. Here we disclose the design and optimization of a series of hydroxamic acids IRAP inhibitors bearing a 5-substituted indole. Docking studies of the best compound <b>43</b> (<b>BDM_92499</b>), a single-digit nanomolar and selective inhibitor of IRAP, suggest an original binding mode and highlight the substituent on the indole and a primary amide as groups driving selectivity. Several inhibitors in the series displayed IRAP-dependent inhibition of antigen cross-presentation. These results pave the way to the development of novel therapeutic agents targeting IRAP.