ANTIRHEUMATIC AGENTS .2. NOVEL METHOTREXATE DERIVATIVES BEARING AN ALKYL-SUBSTITUTED BENZENE-RING

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.