H. Matsuoka et al., ANTIRHEUMATIC AGENTS - NOVEL METHOTREXATE DERIVATIVES BEARING A BENZOXAZINE OR BENZOTHIAZINE MOIETY, Journal of medicinal chemistry, 40(1), 1997, pp. 105-111
Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiaz
ine or dihydro-2H,1,4-benzoxazine were synthesized and tested for in v
itro antiproliferative activities against human synovial cells (hSC) a
nd human peripheral blood mononuclear cells (hPBMC) obtained from pati
ents with rheumatoid arthritis and healthy volunteers, respectively. I
n vivo antiarthritic activities of these derivatives were also evaluat
ed in a rat adjuvant arthritis model. ydro-2H-1,4-benzothiazin-7-yl]ca
rbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative a
ctivities in hSC and hPBMC than MTX in vitro, Antiproliferative activi
ties of ro-2H-1,4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) a
nd -2H-1,4-benzothiazin-7-yl]carbonyl]-L-homoglutamic acid (3d) (MX-68
) were comparable to that of MTX in these in vitro assays. Compounds 3
b,d (MX-68) significantly suppressed progression of the adjuvant arthr
itis in a dose-dependent manner ranging from 0.5 to 2.5 mg/kg (po). In
addition, 3d (MX-68) completely suppressed this progression at the do
se of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and
homoglutamate, as expected, did not undergo polyglutamation, a proces
s which may be responsible for the associated side effects of MTX. The
se results suggest that 3d (MX-68) is a potent and safe candidate anti
rheumatic agent, absent of the side effects of MTX.