Discovery of New 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 43 (BDM_92499), 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.