Analogues of methotrexate in rheumatoid arthritis. 1. Effects of 10- deazaaminopterin analogues on type II collagen-induced arthritis in mice Journal Article
| Authors: | DeGraw, J. I.; Colwell, W. T.; Crase, J.; Smith, R. L.; Piper, J. R.; Waud, W. R.; Sirotnak, F. M. |
| Article Title: | Analogues of methotrexate in rheumatoid arthritis. 1. Effects of 10- deazaaminopterin analogues on type II collagen-induced arthritis in mice |
| Abstract: | 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 α-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 °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. |
| Keywords: | unclassified drug; human cell; drug efficacy; nonhuman; methotrexate; mass spectrometry; animal cell; mouse; animals; mice; cell survival; cell line; animal experiment; animal model; drug potency; drug effect; tumor cells, cultured; drug synthesis; structure activity relation; collagen; magnetic resonance spectroscopy; molecular structure; rheumatoid arthritis; antiinflammatory activity; aminopterin; drug conformation; antirheumatic agents; methotrexate derivative; arthritis, rheumatoid; humans; human; article; n [5 [1 [(2,4 diamino 6 pteridinyl)methyl]propyl] 2 thenoyl]glutamic acid; n [5 [2 (2,4 diamino 6 pteridinyl)ethyl] 2 thenoyl]glutamic acid |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 40 |
| Issue: | 3 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 1997-01-31 |
| Start Page: | 370 |
| End Page: | 376 |
| Language: | English |
| DOI: | 10.1021/jm9505526 |
| PUBMED: | 9022804 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Export Date: 17 March 2017 -- Source: Scopus |
