Analogues of methotrexate in rheumatoid arthritis. 1. Effects of 10-deazaaminopterin analogues on type II collagen-induced arthritis in mice.
Carbonation of the dianions (LDA) of 5-methylthiophene-2-carboxylic, 2-methylpyridine-5-carboxylic, and 3-methylpyridine-6-carboxylic acids provided the respective carboxy heteroarylacetic acids. The crude diacids were directly esterified in MeOH-HCl to afford the diesters. Alkylation of the sodio anions with ethyl iodide yielded the appropriate alpha-ethyl diesters. The anions of the various diester substrates were then alkylated by 2,4-diamino-6-(bromomethyl)-pteridine followed by ester saponification at room temperature to afford the respective 2,4-diamino-4-deoxy-10-carboxy-10-deazapteroic acids. The 10-carboxyl group was readily decarboxylated by heating in DMSO at temperatures of 110-135 degrees C to give the diamino 10-deaza heteropteroic acid intermediates. Coupling with diethyl L-glutamate followed by ester hydrolysis afforded the target aminopterins. The analogues were evaluated for antiinflammatory effect in the mouse type II collagen model. The thiophene analogue of 10-ethyl-10-deazaaminopterin was found to be an effective inhibitor in terms of reduced visual evidence of inflammation and swelling as determined by caliper measurement.
DeGraw
J I
JI
Bio-Organic Chemistry Laboratory, SRI International, Menlo Park, California 94025, USA.
Colwell
W T
WT
Crase
J
J
Smith
R L
RL
Piper
J R
JR
Waud
W R
WR
Sirotnak
F M
FM
D000630:Aminopterin; D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D015394:Molecular Structure; D014407:Tumor Cells, Cultured
D018501:Antirheumatic Agents; C104430:N-(5-(beta-(2,4-diamino-6-pteridinyl)ethyl)-2-thenoyl)glutamic acid; D003094:Collagen; D000630:Aminopterin; D008727:Methotrexate