Affordable Access

deepdyve-link
Publisher Website

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

Authors
  • Korkmaz, Brice1
  • Lesner, Adam2
  • Wysocka, Magdalena2
  • Gieldon, Artur2
  • Håkansson, Maria3
  • Gauthier, Francis4
  • Logan, Derek T3
  • Jenne, Dieter E5
  • Lauritzen, Conni6
  • Pedersen, John7
  • 1 INSERM, UMR 1100, "Centre d'Etude des Pathologies Respiratoires", 37032 Tours, France; Université de Tours, 37032 Tours, France. Electronic address: [email protected] , (France)
  • 2 Faculty of Chemistry, University of Gdansk, 80-308 Gdansk, Poland. , (Poland)
  • 3 SARomics Biostructures, 223 63 Lund, Sweden. , (Sweden)
  • 4 INSERM, UMR 1100, "Centre d'Etude des Pathologies Respiratoires", 37032 Tours, France; Université de Tours, 37032 Tours, France. , (France)
  • 5 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, German Center for Lung Research (DZL), 81377 Munich, Germany; Max Planck Institute of Neurobiology, 82152 Planegg-Martinsried, Germany. , (Germany)
  • 6 Neuprozyme Therapeutics A/S, 2970 Hörsholm, Denmark. , (Denmark)
  • 7 Neuprozyme Therapeutics A/S, 2970 Hörsholm, Denmark. Electronic address: [email protected] , (Denmark)
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
Jun 01, 2019
Volume
164
Pages
349–367
Identifiers
DOI: 10.1016/j.bcp.2019.04.006
PMID: 30978322
Source
Medline
Keywords
Language
English
License
Unknown

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 ((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. Copyright © 2019 Elsevier Inc. All rights reserved.

Report this publication

Statistics

Seen <100 times