Science and Research

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

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.

  • Korkmaz, B.
  • Lesner, A.
  • Wysocka, M.
  • Gieldon, A.
  • Hakansson, M.
  • Gauthier, F.
  • Logan, D. T.
  • Jenne, D. E.
  • Lauritzen, C.
  • Pedersen, J.

Keywords

  • Animals
  • Anti-Asthmatic Agents/*chemistry/pharmacology/*therapeutic use
  • Arthritis, Rheumatoid/*drug therapy/*metabolism
  • Cathepsin C/*antagonists & inhibitors/*metabolism
  • Crystallography, X-Ray/methods
  • Drug Evaluation, Preclinical/methods
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Random Allocation
  • Structure-Activity Relationship
  • U937 Cells
  • *Cathepsin C
  • *Cysteine protease
  • *Inhibitor
  • *Neutrophil
  • *Serine protease
Publication details
DOI: 10.1016/j.bcp.2019.04.006
Journal: Biochem Pharmacol
Pages: 349-367 
Work Type: Original
Location: CPC-M
Disease Area: AA
Partner / Member: LMU
Access-Number: 30978322
See publication on PubMed

DZL Engagements

chevron-down