Linked Life Data

9022805

Source:http://linkedlifedata.com/resource/pubmed/id/9022805

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
1997-3-13
pubmed:abstractText
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.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jan
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
31
pubmed:volume
40
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
377-84
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
1997
pubmed:articleTitle
Analogues of methotrexate in rheumatoid arthritis. 2. Effects of 5-deazaaminopterin, 5,10-dideazaaminopterin, and analogues on type II collagen-induced arthritis in mice.
pubmed:affiliation
Organic Chemistry Department, Southern Research Institute, Birmingham, Alabama 35255, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't