Methotrexate prodrugs sensitive to reactive oxygen species for the improved treatment of rheumatoid arthritis

Research output: Contribution to journalJournal articleResearchpeer-review

  • Nikolaj S. Andersen
  • Jorge Peiró Cadahía
  • Viola Previtali
  • Jon Bondebjerg
  • Christian A. Hansen
  • Hansen, Anders Elias
  • Thomas L. Andresen
  • Mads H. Clausen

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
Pages (from-to)738-746
Number of pages9
Publication statusPublished - 2018

    Research areas

  • Inflammation, Methotrexate, Methotrexate (PubChem CID: 126941), Prodrug, Reactive oxygen species, Rheumatoid arthritis, Thiazolidinone

ID: 220846827