H. Matsuka et al., ANTIRHEUMATIC AGENTS .2. NOVEL METHOTREXATE DERIVATIVES BEARING AN ALKYL-SUBSTITUTED BENZENE-RING, Chemical and Pharmaceutical Bulletin, 44(12), 1996, pp. 2287-2293
Novel methotrexate (MTX) derivatives with either a mono- or dialkyl-su
bstituted benzene ring were synthesized and initially tested for in vi
tro anti-proliferative activities using human peripheral blood mononuc
lear cells (hPBMC) derived from healthy volunteers and synovial cells
(hSC) derived from patients with rheumatoid arthritis (RA). Compounds
with potent activities were further evaluated in an in vivo adjuvant a
rthritis model. In comparison with MTX, a glutamate derivative 3a was
more potent as a suppressor of the in vitro cell proliferation and the
in vivo experimental arthritis, and a homoglutamate derivative, 3e, e
xhibited fairly good activities in vitro and considerable activity in
vivo in a dose-dependent manner, As expected, 3e did not act as a subs
trate of folylpolyglutamate synthetase (FPGS), and thus did not underg
o polyglutamation, which is thought to be responsible for side-effects
that occur during MTX therapy.