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
AbstractCathepsin 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.
|Journal series||Biochemical Pharmacology, ISSN 0006-2952, (A 40 pkt)|
|Publication size in sheets||0.9|
|Keywords in English||Cathepsin C, cysteine protease, neutrophil, serine protease, inhibitor|
|Score||= 40.0, 24-07-2019, ArticleFromJournal|
|Publication indicators||: 2016 = 1.326; : 2017 = 4.235 (2) - 2017=4.752 (5)|
|Citation count*||1 (2019-08-22)|
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.