Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis

A series
of novel hydrogen peroxide sensitive prodrugs of methotrexate
(MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic
efficacy in mice with collagen induced arthritis (CIA) as a model
of chronic rheumatoid arthritis (RA). The prodrug strategy selected
is based on ROS-labile 4-methylphenylboronic acid promoieties linked
to the drugs via a carbamate linkage or a direct C–N bond.
Activation under pathophysiological concentrations of H2O2 proved to be effective, and prodrug candidates were
selected in agreement with relevant in vitro physicochemical
and pharmacokinetic assays. Selected candidates showed moderate to
good solubility, high chemical and enzymatic stability, and therapeutic
efficacy comparable to the parent drugs in the CIA model. Importantly,
the prodrugs displayed the expected safer toxicity profile and increased
therapeutic window compared to MTX and AMT while maintaining a comparable
therapeutic efficacy, which is highly encouraging for future use in
RA patients.