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

Abstract

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
Brice Korkmaz,,
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, 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
Maria Håkansson,,
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, Francis Gauthier
Francis Gauthier,,
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, Derek T. Logan
Derek T. Logan,,
-
, Dieter Jenne
Dieter Jenne,,
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, Conni Lauritzen
Conni Lauritzen,,
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, John Pedersen
John Pedersen,,
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Journal seriesBiochemical Pharmacology, ISSN 0006-2952, (A 40 pkt)
Issue year2019
Vol164
Pages349-367
Publication size in sheets0.9
Keywords in EnglishCathepsin C, cysteine protease, neutrophil, serine protease, inhibitor
ASJC Classification3004 Pharmacology; 1303 Biochemistry
DOIDOI:10.1016/j.bcp.2019.04.006
URL https://doi.org/10.1016/j.bcp.2019.04.006
Languageen angielski
Score (nominal)40
ScoreMinisterial score = 40.0, 24-07-2019, ArticleFromJournal
Publication indicators Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.326; WoS Impact Factor: 2017 = 4.235 (2) - 2017=4.752 (5)
Citation count*1 (2019-08-22)
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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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