TY - JOUR
T1 - Methotrexate prodrugs sensitive to reactive oxygen species for the improved treatment of rheumatoid arthritis
AU - Andersen, Nikolaj S.
AU - Peiró Cadahía, Jorge
AU - Previtali, Viola
AU - Bondebjerg, Jon
AU - Hansen, Christian A.
AU - Hansen, Anders E.
AU - Andresen, Thomas L.
AU - Clausen, Mads H.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Inflammation
KW - Methotrexate
KW - Methotrexate (PubChem CID: 126941)
KW - Prodrug
KW - Reactive oxygen species
KW - Rheumatoid arthritis
KW - Thiazolidinone
U2 - 10.1016/j.ejmech.2018.07.045
DO - 10.1016/j.ejmech.2018.07.045
M3 - Journal article
C2 - 30048923
AN - SCOPUS:85050212430
SN - 0223-5234
VL - 156
SP - 738
EP - 746
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -