Source:http://linkedlifedata.com/resource/pubmed/id/14584938
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
23
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| pubmed:dateCreated |
2003-10-30
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| pubmed:abstractText |
A group of 6-alkyl (alkoxy or alkylthio)-4-aryl-3-(4-methanesulfonylphenyl)pyran-2-ones (14a-v), possessing either a H or F substituent at the para-position of the C-4 phenyl ring, were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo antiinflammatory-analgesic activities. Although 6-ethylthio-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14s) exhibited a very high in vitro COX-2 inhibitory potency (IC(50) = 0.0032 muM) and COX-2 selectivity (SI > 120 000), 14s exhibited moderate antiinflammatory activity compared to celecoxib in a carrageenan-induced rat paw edema assay. In contrast, the less potent (IC(50) = 0.10 muM), and less selective (SI = 2880) COX-2 inhibitor 6-ethoxy-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14i) exhibited good antiinflammatory activity where a 1 mg/kg oral dose reduced inflammation 32 and 67% at 3 and 5 h postdrug administration relative to the reference drug celecoxib where a 50 mg/kg oral dose reduced inflammation by 79 and 58% at the respective 3 and 5 h time periods. Molecular modeling studies, where 14i was docked in the active site of both COX-1 and COX-2, reveals that the C-6 ethoxy substituent orients the pyran-2-one ring to position the SO(2)Me pharmacophore in the vicinity of the secondary pocket in COX-2. The absence of this COX-2 secondary pocket in the COX-1 binding site is due to the presence of the bulky Ile(523) in COX-1 such that access to the amino acid residues (Ile(517), Phe(518), Gln(192), and His(90)), which line the COX-2 secondary pocket with which the SO(2)Me pharmacophore could interact, is hindered. The six-membered pyran-2-one ring system is a suitable central template to design selective COX-2 inhibitors.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Anti-Inflammatory Agents...,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 1,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 2,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase 2 Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclooxygenase Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Prostaglandin-Endoperoxide Synthases,
http://linkedlifedata.com/resource/pubmed/chemical/Ptgs1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrans,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrones,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfones
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| pubmed:status |
MEDLINE
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| pubmed:month |
Nov
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| pubmed:issn |
0022-2623
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| pubmed:author | |
| pubmed:issnType |
Print
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| pubmed:day |
6
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| pubmed:volume |
46
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
4872-82
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| pubmed:dateRevised |
2006-11-15
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| pubmed:meshHeading |
pubmed-meshheading:14584938-Animals,
pubmed-meshheading:14584938-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:14584938-Binding Sites,
pubmed-meshheading:14584938-Cyclooxygenase 1,
pubmed-meshheading:14584938-Cyclooxygenase 2,
pubmed-meshheading:14584938-Cyclooxygenase 2 Inhibitors,
pubmed-meshheading:14584938-Cyclooxygenase Inhibitors,
pubmed-meshheading:14584938-Drug Design,
pubmed-meshheading:14584938-Edema,
pubmed-meshheading:14584938-Isoenzymes,
pubmed-meshheading:14584938-Membrane Proteins,
pubmed-meshheading:14584938-Models, Molecular,
pubmed-meshheading:14584938-Pain Measurement,
pubmed-meshheading:14584938-Prostaglandin-Endoperoxide Synthases,
pubmed-meshheading:14584938-Pyrans,
pubmed-meshheading:14584938-Pyrones,
pubmed-meshheading:14584938-Rats,
pubmed-meshheading:14584938-Structure-Activity Relationship,
pubmed-meshheading:14584938-Sulfones
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| pubmed:year |
2003
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| pubmed:articleTitle |
Design, synthesis, and biological evaluation of 6-substituted-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: a novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors.
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| pubmed:affiliation |
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, T6G 2N8, Canada.
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| pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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