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

08:00 EDT 20th July 2018 | BioPortfolio

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

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 HO, we propose to improve treatment through site-selective delivery of MTX to inflammatory tissue by use of a HO sensitive MTX prodrug. To establish proof proof-of-concept, two novel HO 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 HO. 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.

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Journal Details

This article was published in the following journal.

Name: European journal of medicinal chemistry
ISSN: 1768-3254
Pages: 738-746

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