title: Analogues of methotrexate in rheumatoid arthritis. 2. Effects of 5-deazaaminopterin, 5,10-dideazaaminopterin, and analogues on type II collagen-induced arthritis in mice.
abstract: Twenty-six compounds derived from the 5-deaza- and 5,10-dideazaaminopterin series of aminopterin analogues were evaluated for antiarthritic activity in the mouse type II collagen model. New compounds in the 5-deaza series were prepared by alkylation of an appropriate N-substituted (4-aminobenzoyl)-L-glutamic acid dialkyl ester or N-(5-amino-2-thenoyl)-L-glutamate diester with a 2,4-diamino-5-alkyl-6-(bromomethyl)-5-deazapteridine. The resultant 5-deazaaminopterin diesters were saponified to provide the target 5-deaza analogues. 5,10-Dideazaaminopterins were synthesized by similar alkylation of the carbanions of appropriate 4-carboxyphenylacetic, (5-carboxy-2-thienyl)acetic, or (5-carboxy-2-pyridyl)acetic acid dimethyl esters. The diesters of the 2,4-diamino-4-deoxy-10-carboxy-5,10-dideazapteroic acid types so obtained were saponified and then readily decarboxylated by heating in Me2SO solution to provide the 2,4-diamino-5,10-dideazapteroic acid-type intermediates. Peptide coupling with diethyl L-glutamate followed by ester hydrolysis at room temperature afforded the new 5,10-dideazaaminopterin analogues. 5-Deazaaminopterins bearing an alkyl substituent at the 5-position were generally quite effective as antiinflammatory agents. Thus 5-propyl-5-deazaaminopterin, 5-methyl-10-propargyl-5-deazaaminopterin, 5-methyl-10-allyl-5-deazaaminopterin, 5-ethyl-5-deazamethotrexate, and 2,5-disubstituted thiophene analogue of 5-methyl-5-deazaaminopterin showed potencies greater than methotrexate by intraperitoneal or oral administration and were active over a considerably broader dose range. Useful activity in the 5,10-dideaza series was only observed for 5,10-dideazaaminopterin and its 10-methyl analogue. Alkyl substitution at C-5 or C-10 was generally detrimental to antiinflammatory activity in this series.
authors.affiliation: Organic Chemistry Department, Southern Research Institute, Birmingham, Alabama 35255, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Piper
authors.forename: J I
authors.initials: JI
authors.lastname: DeGraw
authors.forename: W T
authors.initials: WT
authors.lastname: Colwell
authors.forename: C A
authors.initials: CA
authors.lastname: Johnson
authors.forename: R L
authors.initials: RL
authors.lastname: Smith
authors.forename: W R
authors.initials: WR
authors.lastname: Waud
authors.forename: F M
authors.initials: FM
authors.lastname: Sirotnak
mesh_terms: D000630:Aminopterin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D018501:Antirheumatic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D014407:Tumor Cells, Cultured
chemical_list: D018501:Antirheumatic Agents; C040506:5-deazaaminopterin; D003094:Collagen; D000630:Aminopterin; D008727:Methotrexate