title: Antirheumatic agents. I. Novel methotrexate derivatives bearing an indoline moiety.
abstract: Various novel methotrexate (MTX) derivatives bearing an indoline moiety were synthesized and tested for biological activities using human peripheral blood mononuclear cell (hPBMC) and human synovial cells (hSC) derived from patients with rheumatoid arthritis (RA). Compounds having potent activity in vitro were further evaluated using an adjuvant arthritis model in vivo. N-[1-(2,4-Diamino-6-pteridinylmethyl)indoline-5-carbonyl]-L-glutam ic acid 2f showed more potent activities than MTX in vitro and in vivo, and N-[1-(2,4-diamino-6-pteridinylmethyl)-indoline-5-carbonyl]-L-2-ami noadipic acid 2d exhibited fairly good activities in vitro and considerable activity in vivo. Compound 2d was, as expected, not sensitive to folyl-polyglutamate synthetase (FPGS) and did not undergo polyglutamation, a process which may be responsible for a side-effect during MTX therapy.
authors.affiliation: Fuji-Gotemba Laboratories Chugai Pharmaceutical, Co., Ltd., Shizuoka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Matsuoka
authors.forename: N
authors.initials: N
authors.lastname: Kato
authors.forename: K
authors.initials: K
authors.lastname: Tsuji
authors.forename: N
authors.initials: N
authors.lastname: Maruyama
authors.forename: H
authors.initials: H
authors.lastname: Suzuki
authors.forename: M
authors.initials: M
authors.lastname: Mihara
authors.forename: Y
authors.initials: Y
authors.lastname: Takeda
authors.forename: K
authors.initials: K
authors.lastname: Yano
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D013583:Synovial Membrane / Q000187:drug effects
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate