ArticlePharmaceuticals (Basel, Switzerland)2021
Discovery and Optimization of Selective Inhibitors of Meprin α (Part I).
Article in Pharmaceuticals (Basel, Switzerland), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed, 8 citations in OpenAlex.
- Synthesis and structure-activity relationships of pyrazole-based inhibitors of meprin α and β.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Snakebite drug discovery: high-throughput screening to identify novel snake venom metalloproteinase toxin inhibitors.Frontiers in pharmacology · 2023Article
- Helical ultrastructure of the metalloprotease meprin α in complex with a small molecule inhibitor.Nature communications · 2022Article
- Discovery and Optimization of Selective Inhibitors of Meprin α (Part II).Pharmaceuticals (Basel, Switzerland) · 2021Article
Corrections and comments
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Authors and funding
9 authors at 4 institutions in 2 countries.
Funding
Abstract
Meprin α and β are zinc-dependent proteinases implicated in multiple diseases including cancers, fibrosis, and Alzheimer's. However, until recently, only a few inhibitors of either meprin were reported and no inhibitors are in preclinical development. Moreover, inhibitors of other metzincins developed in previous years are not effective in inhibiting meprins suggesting the need for de novo discovery effort. To address the paucity of tractable meprin inhibitors we developed ultrahigh-throughput assays and conducted parallel screening of >650,000 compounds against each meprin. As a result of this effort, we identified five selective meprin α hits belonging to three different chemotypes (triazole-hydroxyacetamides, sulfonamide-hydroxypropanamides, and phenoxy-hydroxyacetamides). These hits demonstrated a nanomolar to micromolar inhibitory activity against meprin α with low cytotoxicity and >30-fold selectivity against meprin β and other related metzincincs. These selective inhibitors of meprin α provide a good starting point for further optimization.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.