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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
18
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pubmed:dateCreated |
2001-8-24
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pubmed:abstractText |
This paper describes the synthesis of a series of azo compounds able to deliver 5-aminosalicylic acid (5-ASA) and a potent platelet activating factor (PAF) antagonist in a colon-specific manner for the purpose of treating ulcerative colitis. We found it possible to add an amino group on the aromatic moiety of our reported 1-[(1-acyl-4-piperidyl)methyl]-1H-2-methylimidazo[4,5-c]pyridine derivatives or on British Biotech compounds BB-882 and BB-823 maintaining a high level of activity as PAF antagonist. A selected compound UR-12715 (49c) showed an IC(50) of 8 nM in the in vitro PAF-induced aggregation assay, and an ID(50) of 29 microg/kg in the in vivo PAF-induced hypotension test in normotensive rats. Through attachment of 49c to the 5-ASA via azo functionality we obtained UR-12746 (70). Pharmacokinetics experiments with [14C]-70 allow us to reach the following conclusions, critical in the design of these new prodrugs of 5-ASA. Neither the whole molecule 70 nor the carrier 49c were absorbed after oral administration of [14C]-70 in rat as was demonstrated by the absence of plasma levels of radioactivity and the high recovery of it in feces. Effective cleavage of azo bond (84%) by microflora in the colon is achieved. These facts ensure high topical concentrations of 5-ASA and 49c in the colon. Additionally, 70 exhibited a potent anticolitic effect in the trinitrobenzenesulfonic acid-induced colitis model in the rat. This profile suggests that UR-12746 (70) provides an attractive new approach to the treatment of ulcerative colitis.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Amines,
http://linkedlifedata.com/resource/pubmed/chemical/Aminosalicylic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Inflammatory Agents...,
http://linkedlifedata.com/resource/pubmed/chemical/Aza Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Azo Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Imidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Mesalamine,
http://linkedlifedata.com/resource/pubmed/chemical/Platelet Activating Factor,
http://linkedlifedata.com/resource/pubmed/chemical/Prodrugs,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Trinitrobenzenesulfonic Acid,
http://linkedlifedata.com/resource/pubmed/chemical/UR 12746
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0022-2623
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:day |
30
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pubmed:volume |
44
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3001-13
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pubmed:dateRevised |
2004-11-17
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pubmed:meshHeading |
pubmed-meshheading:11520209-Amines,
pubmed-meshheading:11520209-Aminosalicylic Acids,
pubmed-meshheading:11520209-Animals,
pubmed-meshheading:11520209-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:11520209-Aza Compounds,
pubmed-meshheading:11520209-Azo Compounds,
pubmed-meshheading:11520209-Colitis, Ulcerative,
pubmed-meshheading:11520209-Drug Evaluation, Preclinical,
pubmed-meshheading:11520209-Female,
pubmed-meshheading:11520209-Hypotension,
pubmed-meshheading:11520209-Imidazoles,
pubmed-meshheading:11520209-Male,
pubmed-meshheading:11520209-Mesalamine,
pubmed-meshheading:11520209-Platelet Activating Factor,
pubmed-meshheading:11520209-Platelet Aggregation,
pubmed-meshheading:11520209-Prodrugs,
pubmed-meshheading:11520209-Pyridines,
pubmed-meshheading:11520209-Rats,
pubmed-meshheading:11520209-Rats, Sprague-Dawley,
pubmed-meshheading:11520209-Rats, Wistar,
pubmed-meshheading:11520209-Stereoisomerism,
pubmed-meshheading:11520209-Structure-Activity Relationship,
pubmed-meshheading:11520209-Trinitrobenzenesulfonic Acid
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pubmed:year |
2001
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pubmed:articleTitle |
Novel azo derivatives as prodrugs of 5-aminosalicylic acid and amino derivatives with potent platelet activating factor antagonist activity.
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pubmed:affiliation |
Research Center, J. Uriach & Cía.S.A., Degà Bahí 59-67, 08026 Barcelona, Spain. chem-carceller@uriach.com
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pubmed:publicationType |
Journal Article
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