title: Polyglutamation of a novel antifolate, MX-68, is not necessary for its anti-arthritic effect.
abstract: N-[[4-[(2,4-diaminopteridin-6-yl)methyl]-3,4-dihydro-2H-1,4-benzothiazin-7-yl]-carbonyl]-L-homoglutamic acid (MX-68), a derivative of methotrexate, was chemically designed to resist polyglutamation and to have a high affinity for dihydrofolate reductase, in an attempt to reduce the side effects of methotrexate. We confirmed that MX-68 did not undergo polyglutamation and investigated the pharmacological activities of MX-68 compared with methotrexate. (1) In vitro: MX-68 inhibited the activity of dihydrofolate reductase to the same degree as methotrexate-tetraglutamate. MX-68 treatment produced a similar anti-proliferative effect to that of methotrexate. However, the intracellular concentration of MX-68 was much lower than the sum of the levels of methotrexate and its polyglutamate, and the effects of MX-68 disappeared when it was removed from the culture medium. (2) In vivo: Oral administration of MX-68 suppressed the development of collagen-induced arthritis in mice and adjuvant-induced arthritis in rats, in a similar fashion to that of methotrexate. These results indicate that polyglutamation is not essential for the anti-arthritic effect of antifolates.
authors.affiliation: Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co., Ltd., 1-135, Komakado, Gotemba, 412-8513, Shizuoka, Japan. urakawakzm@chugai-pharm.co.jp
authors.forename: Kazumi
authors.initials: K
authors.lastname: Urakawa
authors.forename: Masahiko
authors.initials: M
authors.lastname: Mihara
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Takagi
authors.forename: Akinori
authors.initials: A
authors.lastname: Kawamura
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Akamatsu
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Takeda
mesh_terms: D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005493:Folic Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008811:Mice, Inbred DBA; D010453:Peptide Synthases / Q000378:metabolism; D011099:Polyglutamic Acid / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D013379:Substrate Specificity; D013762:Tetrahydrofolate Dehydrogenase / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D018501:Antirheumatic Agents; D005493:Folic Acid Antagonists; C104193:N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro -2H-1,4-benzothiazine-7-carbonyl)-L-2-aminoadipic acid; D015074:2-Aminoadipic Acid; D011099:Polyglutamic Acid; D013762:Tetrahydrofolate Dehydrogenase; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D008727:Methotrexate