1. Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C.
- Author
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Korkmaz, Brice, Lesner, Adam, Wysocka, Magdalena, Gieldon, Artur, Håkansson, Maria, Gauthier, Francis, Logan, Derek T., Jenne, Dieter E., Lauritzen, Conni, and Pedersen, John
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ELASTASES , *BONE marrow cells , *CYCLOPROPYL compounds , *BONE marrow , *RHEUMATOID arthritis , *AUTOIMMUNE diseases - 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, IcatC XPZ-01 ((S)-2-amino-N-((1 R ,2 R)-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 XPZ-01 accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatC XPZ-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. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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