Methotrexate Prodrugs Sensitive to Reactive Oxygen Species for the Improved Treatment of Rheumatoid Arthritis

Nikolaj S. Andersen, Jorge Peiro Cadahia, Viola Previtali, Jon Bondebjerg, Christian A. Hansen, Anders E. Hansen, Thomas Lars Andresen, Mads H. Clausen*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Methotrexate (MTX) is the standard of care in the treatment of rheumatoid arthritis (RA), a common autoimmune disease that is characterized by chronic inflammation in the synovial membrane of joints. Unfortunately, MTX suffers from high discontinuation rates due to a large variability in efficacy and, in particular, adverse effects. As inflammation is associated with elevated levels of reactive oxygen species (ROS) like H2O2, we propose to improve treatment through site-selective delivery of MTX to inflammatory tissue by use of a H2O2 sensitive MTX prodrug. To establish proof proof-of-concept, two novel H2O2 sensitive, thiazolidinone-based MTX prodrugs were synthesized and evaluated for this purpose. MTX-γ-thiazolidinone (MTX-γ-TZ) exhibited the most promising properties – good to high chemical and metabolic stability, excellent aqueous solubility, while being activated when subjected to patho-physiological concentrations of H2O2. In vivo, MTX-γ-TZ exhibited comparable efficacy to MTX in a murine collagen type II-induced arthritis (CIA) model while treated mice showed indications of reduced toxicity as their body weight decreased less towards the end of the study, compared to the MTX-treated group
Original languageEnglish
JournalEuropean Journal of Medicinal Chemistry
Volume156
Pages (from-to)738-746
ISSN0223-5234
DOIs
Publication statusPublished - 2018

Keywords

  • Rheumatoid arthritis
  • Inflammation
  • Methotrexate
  • Reactive oxygen species
  • Prodrug
  • Thiazolidinone

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