SYNTHESIS AND EVALUATION OF NOVEL FLUORINATED METHOTREXATE DERIVATIVES FOR APPLICATION TO RHEUMATOID-ARTHRITIS TREATMENT

An ongoing search for new antifolate drugs useful against rheumatoid a rthritis (RA) led us to prepare new methotrexate (MTX) derivatives con taining enantiomerically pure L-erythro- or L-threo-gamma-fluoroglutam ic acid. The derivatives in which the phenyl ring was replaced by a 3' -substituted phenyl or methylthiophene ring skewed potent immunosuppre ssive activities, including in vitro inhibition of mitogen responses o f both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant a rthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong eiectronegativity of fluorine, which incre ases the acidity of the gamma-carboxyl group and thereby decreases pol yglutamylation in normal cells. These results revealed the potential o f the fluorinated MTX derivatives as candidate drugs for the treatment of RA.