Synthesis and Structure-Activity Relationships of Pyrazole-based Inhibitors of Meprin α and β

Targeting metalloproteinases has been in focus of drug design for a long time. However, human proteinases of the astacin family, in particular meprin α and β emerged as potential drug targets just recently. More and more data links them to several diseases with different pathological background. Nevertheless, the validation of meprins as suitable drug targets requires highly potent and selective inhibitors as chemical probes to elucidate their role in pathophysiology. Albeit highly selective inhibitors of meprin β have already been reported, only inhibitors of meprin α with modest activity or selectivity are known. Starting from recently reported heteroaromatic scaffolds, the aim of this study was the optimization of meprin α and/or meprin β inhibition while keeping the favorable off-target inhibition profile over other metalloproteases. We now report novel potent pan-meprin inhibitors as well as highly active inhibitors of meprin α with superior selectivity over meprin β. The latter are suitable to serve as chemical probes and enable further target validation of meprin proteases.