Analogues of Methotrexate in Rheumatoid Arthritis. 1. Effects of 10-Deazaaminopterin Analogues on Type II Collagen-Induced Arthritis in Mice

• Published in: Journal of medicinal chemistry Vol. 40; no. 3; pp. 370 - 376
• Main Authors: DeGraw, Joseph I, Colwell, William T, Crase, Jac, Smith, R. Lane, Piper, James R, Waud, William R, Sirotnak, Francis M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 31.01.1997; Amer Chemical Soc
• Subjects: Aminopterin; Animals; Antirheumatic Agents - chemical synthesis; Antirheumatic Agents - chemistry; Antirheumatic Agents - pharmacology; Antirheumatic Agents - therapeutic use; Arthritis, Rheumatoid - drug therapy; Biological and medical sciences; Cell Line; Cell Survival - drug effects; Chemistry, Medicinal; Collagen; Humans; Immunomodulators; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Medical sciences; Methotrexate - analogs & derivatives; Methotrexate - chemistry; Methotrexate - pharmacology; Methotrexate - therapeutic use; Mice; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Tumor Cells, Cultured; TRIAL; PULSE METHOTREXATE; THERAPY; EFFICACY; MOLECULE; Diseases of the osteoarticular system; Cytotoxicity; Arthritis; Inflammatory joint disease; Thiophene derivatives; Structure activity relation; Established cell line; Antirheumatic agent; Mechanism of action; Methotrexate; Chemical synthesis; Rodentia; Antiinflammatory agent; Pteridine derivatives; In vitro; Vertebrata; Chemotherapy; Sulfur heterocycle; Experimental disease; Mammalia; Treatment; Mouse; Animal; Rheumatoid arthritis; Immunosuppressive agent
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9505526

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.