title: Antirheumatic agents: novel methotrexate derivatives bearing a benzoxazine or benzothiazine moiety.
abstract: Novel methotrexate (MTX) derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H-1,4-benzoxazine were synthesized and tested for in vitro antiproliferative activities against human synovial cells (hSC) and human peripheral blood mononuclear cells (hPBMC) obtained from patients with rheumatoid arthritis and healthy volunteers, respectively. In vivo antiarthritic activities of these derivatives were also evaluated in a rat adjuvant arthritis model. N-[[4-[(2,4-Diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzothiazin-7-yl]carbonyl]-L-glutamic acid (3c) exhibited more potent antiproliferative activities in hSC and hPBMC than MTX in vitro. Antiproliferative activities of N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1, 4-benzoxazin-7-yl]carbonyl]-L-homoglutamic acid (3b) and N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-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 3b,d (MX-68) significantly suppressed progression of the adjuvant arthritis 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 dose of 2.5 mg/kg (po). Importantly, 3d (MX-68) having benzothiazine and homoglutamate, as expected, did not undergo polyglutamation, a process which may be responsible for the associated side effects of MTX. These results suggest that 3d (MX-68) is a potent and safe candidate antirheumatic agent, absent of the side effects of MTX.
authors.affiliation: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Company, Ltd., Shizuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Matsuoka
authors.forename: N
authors.initials: N
authors.lastname: Ohi
authors.forename: M
authors.initials: M
authors.lastname: Mihara
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Miyamoto
authors.forename: N
authors.initials: N
authors.lastname: Maruyama
authors.forename: K
authors.initials: K
authors.lastname: Tsuji
authors.forename: N
authors.initials: N
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Akimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Takeda
authors.forename: K
authors.initials: K
authors.lastname: Yano
authors.forename: T
authors.initials: T
authors.lastname: Kuroki
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000737:chemistry* / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000737:chemistry* / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects; D010078:Oxazines / Q000737:chemistry*; D051381:Rats; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects; D013843:Thiazines / Q000737:chemistry*
chemical_list: D018501:Antirheumatic Agents; D010078:Oxazines; D013843:Thiazines; D008727:Methotrexate