Targeting proteases has always been a source for new therapeutics. For example, huge efforts have been made to develop inhibitors of metalloproteases, in particular matrix metalloproteases. However, many candidates failed, most likely due to a poor selectivity profile leading to undesired side effects. A family of metalloproteases closely related to the MMPs are the astacins. However these proteases are not well explored with small molecule probes, yet. In particular Meprin α and β evolved as potential drug targets in the recent years, but the lack of selective inhibitors hampered the detailed investigation of the proteases in different diseases. Thus, our aim was to develop novel selective effectors of both, Meprin α and β. Starting from NNGH, a known Meprin and MMP inhibitor, the first SAR was investigated. This led to a first series of compounds, already exhibiting a good selectivity over related metalloproteases. Here we present a structure-guided optimization, giving rise to a second generation of Meprin inhibitors with improved activity and a remarkable selectivity profile. The design, SAR and fine-tuning of Meprin α and Meprin β inhibition will be shown. The resulting inhibitors will serve as tool compounds and could be used to probe the Meprin proteases in various disease models.

Towards selective inhibitors of the astacin proteases Meprin α and β

255th National Meeting (2018)

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