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

Korkmaz, Brice ; Lesner, Adam ; Wysocka, Magdalena ; Gieldon, Artur ; Håkansson, Maria LU ; Gauthier, Francis ; Logan, Derek T. LU orcid ; Jenne, Dieter E. ; Lauritzen, Conni and Pedersen, John (2019) In Biochemical Pharmacology 164. p.349-367
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... (More)

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.

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author
; ; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cathepsin C, Cysteine protease, Inhibitor, Neutrophil, Serine protease
in
Biochemical Pharmacology
volume
164
pages
19 pages
publisher
Elsevier
external identifiers
  • pmid:30978322
  • scopus:85065203547
ISSN
0006-2952
DOI
10.1016/j.bcp.2019.04.006
language
English
LU publication?
no
additional info
Publisher Copyright: © 2019 Elsevier Inc.
id
04690e12-8ac6-4e6a-8c79-b709d932a777
date added to LUP
2022-04-08 08:52:39
date last changed
2024-06-10 05:07:12
@article{04690e12-8ac6-4e6a-8c79-b709d932a777,
  abstract     = {{<p>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, IcatC<sub>XPZ-01</sub> ((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 IcatC<sub>XPZ-01</sub> accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatC<sub>XPZ-01</sub> 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.</p>}},
  author       = {{Korkmaz, Brice and Lesner, Adam and Wysocka, Magdalena and Gieldon, Artur and Håkansson, Maria and Gauthier, Francis and Logan, Derek T. and Jenne, Dieter E. and Lauritzen, Conni and Pedersen, John}},
  issn         = {{0006-2952}},
  keywords     = {{Cathepsin C; Cysteine protease; Inhibitor; Neutrophil; Serine protease}},
  language     = {{eng}},
  pages        = {{349--367}},
  publisher    = {{Elsevier}},
  series       = {{Biochemical Pharmacology}},
  title        = {{Structure-based design and <i>in vivo</i> anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C}},
  url          = {{http://dx.doi.org/10.1016/j.bcp.2019.04.006}},
  doi          = {{10.1016/j.bcp.2019.04.006}},
  volume       = {{164}},
  year         = {{2019}},
}