Metalloproteinases of the astacin family are drawing ever increasing attention as potential drug targets. However, knowledge regarding inhibitors thereof is limited in most cases. Crucial for the development of metalloprotease inhibitors is high selectivity, to avoid side effects brought about by inhibition of off-target proteases and interference with physiological pathways. In this study we aimed at the design of novel selective inhibitors for the astacin proteinase meprin α. Based on a recently identified tertiary amine scaffold, a series of compounds was synthesized and evaluated. The compounds exhibit reasonable inhibitory activity with high selectivity over other metalloproteases. The isoenzyme meprin β is only slightly inhibited. Hence, the present study revealed a novel class of selective meprin α inhibitors with improved selectivity over known compounds.
Astacin metalloproteinases, in particular meprins α and β, as well as ovastacin, are emerging drug targets. Drug‐discovery efforts have led to the development of the first potent and selective inhibitors in the last few years. However, the most recent compounds are based on a highly flexible tertiary amine scaffold that could cause metabolic liabilities or decreased potency due to the entropic penalty upon binding to the target. Thus, the aim of this study was to discover novel conformationally constrained scaffolds as starting points for further inhibitor optimization. Shifting from flexible tertiary amines to rigid heteroaromatic cores resulted in a boost in inhibitory activity. Moreover, some compounds already exhibited higher activity against individual astacin proteinases compared to recently reported inhibitors and also a favorable off‐target selectivity profile, thus qualifying them as very suitable chemical probes for target validation.
Despite huge progress in hormonal therapy and improved
in vitro
fertilization methods, the success rates in infertility treatment are still limited. A recently discovered mechanism revealed the interplay between the plasma protein fetuin‐B and the cortical granule‐based proteinase ovastacin to be a novel key mechanism in the regulation of fertilization. Upon sperm–egg fusion, cleavage of a distinct zona pellucida component by ovastacin destroys the sperm receptor, enhances zona robustness, and eventually provides a definitive block against polyspermy. An untimely onset of this zona hardening prior to fertilization would consequently result in infertility. Physiologically, this process is controlled by fetuin‐B, an endogenous ovastacin inhibitor. Here we aimed to discover small‐molecule inhibitors of ovastacin that could mimic the effect of fetuin‐B. These compounds could be useful lead structures for the development of specific ovastacin inhibitors that can be used in infertility treatment or
in vitro
fertilization
<p>Despite huge progress in
hormonal therapy and improved in vitro fertilization methods, the
success rates in infertility treatment are still limited. A recently
discovered mechanism revealed the interplay between the plasma protein
fetuin-B and the cortical granule-based proteinase ovastacin as novel
key-mechanism in the regulation of fertilization. Upon sperm-egg fusion,
cleavage of a distinct zona pellucida component by ovastacin destroys
the sperm receptor, enhances zona robustness and eventually provides a
definitive block against polyspermy. An untimely onset of this zona
hardening prior to fertilization would consequently result in
infertility. Physiologically, this process is controlled by fetuin-B, an
endogenous ovastacin inhibitor. Here we aimed at the discovery of small
molecular inhibitors of ovastacin that could mimic the effect of
fetuin-B. Hence, these compounds could be useful lead structures for the
development of specific ovastacin inhibitors that can be utilized in
infertility treatment or in vitro fertilization.</p>
Targeting metalloproteinases has been in the focus of drug design for a long time. However, meprin α and β emerged as potential drug targets just recently and are linked to several diseases with different pathological background. Nevertheless, the validation of meprins as suitable drug targets still 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 optimisation of meprin α and/or meprin β inhibition while keeping the favourable off-target inhibition profile over other metalloproteases. We report 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.
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