Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C
(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
- Korkmaz, Brice ; Lesner, Adam ; Wysocka, Magdalena ; Gieldon, Artur ; Håkansson, Maria LU ; Gauthier, Francis ; Logan, Derek T. LU ; Jenne, Dieter E. ; Lauritzen, Conni and Pedersen, John
- publishing date
- 2019-06
- 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
-
- scopus:85065203547
- pmid:30978322
- 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
- 2024-09-01 10:24:51
@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}}, }