Inhibition of insulin-regulated aminopeptidase (IRAP) activity in the brain leads to facilitation of memory and reversal of memory loss. In a range of memory paradigms, specific, peptide inhibitors of IRAP (angiotensin IV and LVV-hemorphin 7) enhance memory in rats and attenuate memory deficits induced by either bilateral perforant pathway lesions or scopolamine treatment. IRAP is therefore an innovative target for the development of a new class of drugs for the treatment of memory impairment. However, the current peptide inhibitors of IRAP are of limited use for the development of clinically useful therapeutic agents.
We have overcome this problem by identifying a new family of small molecule, IRAP inhibitors suitable for therapeutic drug development. We achieved this significant milestone by in silico screening of compound databases utilizing a molecular model of the catalytic domain of IRAP. We identified a family of compounds designated the HF14 family that exhibited low micromolar affinity (Ki = 2.5-30 µM) in inhibiting the catalytic activity of IRAP. Importantly, the HF14 compounds meet the criteria for further medicinal drug development. The inhibitory effect of the HF14 compounds is specific for IRAP. We have demonstrated that they do not behave in a promiscuous fashion nor do they inhibit the enzymatic activity of other metallopeptidases including aminopeptidases belonging to the same family as IRAP (e.g. aminopeptidase A and N). Initial toxicity tests on cell lines and in anaesthetized animal preparations reveal that the inhibitors demonstrate no cytotoxic effects up to millimolar concentrations. In addition the compounds are amenable to medicinal chemistry modifications.