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The inhibition of this cysteine protease therefore is an interesting therapeutic approach for the treatment of inflammatory disorders with a high neutrophil burden such as COPD. Based on E\u201064c\u2010hydrazide as lead structure, we have recently developed a covalently acting cathepsin C inhibitor using a <jats:italic>n<\/jats:italic>\u2010butyl residue attached at the amine nitrogen of the hydrazide moiety to efficiently address the deep hydrophobic S2 pocket. To further optimize the affinity and selectivity profile of this inhibitor, the S1\u2019\u2010S2\u2019 area was now investigated by a combinatorial approach, showing that Nle\u2010tryptamide is a ligand superior to the initially used Leu\u2010isoamylamide. Using the neutrophil precursor line U937 as a cell culture model, this optimized inhibitor blocks the intracellular cathepsin C activity and thereby suppresses the activation of neutrophil elastase.<\/jats:p>","DOI":"10.1002\/cmdc.202300218","type":"journal-article","created":{"date-parts":[[2023,7,10]],"date-time":"2023-07-10T04:03:57Z","timestamp":1688961837000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["E\u201064c\u2010Hydrazide Based Cathepsin C Inhibitors: Optimizing the Interactions with the S1\u2019\u2010S2\u2019 Area"],"prefix":"10.1002","volume":"18","author":[{"given":"Nora","family":"Tromsdorf","sequence":"first","affiliation":[{"name":"Fakult\u00e4t f\u00fcr Chemie Hochschule Aalen  Beethovenstra\u00dfe 1 73430 Aalen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabian T. 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