Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C

Brice Korkmaz , Adam Lesner , Magdalena Wysocka , Artur Giełdoń , Maria Håkansson , Francis Gauthier , Derek T. Logan , Dieter Jenne , Conni Lauritzen , John Pedersen


Cathepsin C (CatC) is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive protease activities in various neutrophil mediated diseases. We designed and synthesized a series of dipeptidyl cyclopropyl nitrile compounds as putative CatC inhibitors. One compound, IcatCXPZ-01 ((S)-2-amino-N-((1R,2R)-1-cyano-2-(4’-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)cyclopropyl)butanamide)) was identified as a potent inhibitor of both human and rodent CatC. In mice, pharmacokinetic studies revealed that IcatCXPZ-01 accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatCXPZ-01 in a monoclonal anti-collagen antibody induced mouse model of rheumatoid arthritis resulted in statistically significant anti-arthritic activity with persistent decrease in arthritis scores and paw thickness.
Author Brice Korkmaz - [Inserm]
Brice Korkmaz,,
, Adam Lesner (FCh / DET / LBAN)
Adam Lesner,,
- Laboratory of Biochemical Analytics and Nanodiagnostics
, Magdalena Wysocka (FCh / DBCh / LMCh)
Magdalena Wysocka,,
- Laboratory of Medical Chemistry
, Artur Giełdoń (FCh / DTCh / LSP)
Artur Giełdoń,,
- Laboratory of Simulation of Polymers
, Maria Håkansson - [Saromics Biostructures AB]
Maria Håkansson,,
, Francis Gauthier - [Inserm]
Francis Gauthier,,
, Derek T. Logan - [Saromics Biostructures AB]
Derek T. Logan,,
, Dieter Jenne - [Member of the German Center for Lung Research (DZL)]
Dieter Jenne,,
, Conni Lauritzen - [Neuprozyme Therapeutics and Unizyme Laboratories A/S]
Conni Lauritzen,,
, John Pedersen - [Neuprozyme Therapeutics and Unizyme Laboratories A/S]
John Pedersen,,
Journal seriesBiochemical Pharmacology, ISSN 0006-2952, (N/A 100 pkt)
Issue year2019
Publication size in sheets0.9
Keywords in EnglishCathepsin C, cysteine protease, neutrophil, serine protease, inhibitor
ASJC Classification3004 Pharmacology; 1303 Biochemistry
Languageen angielski
Score (nominal)100
Score sourcejournalList
ScoreMinisterial score = 100.0, 06-12-2019, ArticleFromJournal
Publication indicators WoS Citations = 1; Scopus Citations = 1; Scopus SNIP (Source Normalised Impact per Paper): 2018 = 1.161; WoS Impact Factor: 2018 = 4.825 (2) - 2018=4.637 (5)
Citation count*1 (2019-12-09)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
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