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rdf:type |
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lifeskim:mentions |
umls-concept:C0030005,
umls-concept:C0038477,
umls-concept:C0205177,
umls-concept:C0205314,
umls-concept:C0205531,
umls-concept:C0205549,
umls-concept:C0220781,
umls-concept:C0220825,
umls-concept:C0226896,
umls-concept:C0442027,
umls-concept:C0456387,
umls-concept:C0679622,
umls-concept:C1257954,
umls-concept:C1515655,
umls-concept:C1527415,
umls-concept:C1883254
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pubmed:issue |
7
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pubmed:dateCreated |
1999-5-20
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pubmed:abstractText |
Selective cyclooxygenase-2 (COX-2) inhibitors have been shown to be potent antiinflammatory agents with fewer side effects than currently marketed nonsteroidal antiinflammatory drugs (NSAIDs). Initial mass screening and subsequent structure-activity relationship (SAR) studies have identified 4b (PD138387) as the most potent and selective COX-2 inhibitor within the thiazolone and oxazolone series of di-tert-butylphenols. Compound 4b has an IC50 of 1.7 microM against recombinant human COX-2 and inhibited COX-2 activity in the J774A.1 cell line with an IC50 of 0.17 microM. It was inactive against purified ovine COX-1 at 100 microM and did not inhibit COX-1 activity in platelets at 20 microM. Compound 4b was also orally active in vivo with an ED40 of 16 mg/kg in the carrageenan footpad edema (CFE) assay and caused no gastrointestinal (GI) damage in rats at the dose of 100 mg/kg but inhibited gastric prostaglandin E2 (PGE2) production in rats' gastric mucosa by 33% following a dose of 100 mg/kg. The SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes. A simple isosteric replacement led to the reversal of selectivity.
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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/Anti-Inflammatory Agents...,
http://linkedlifedata.com/resource/pubmed/chemical/Carrageenan,
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/Dinoprostone,
http://linkedlifedata.com/resource/pubmed/chemical/Isoenzymes,
http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Oxazoles,
http://linkedlifedata.com/resource/pubmed/chemical/PD 138387,
http://linkedlifedata.com/resource/pubmed/chemical/PTGS1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/PTGS2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Phenols,
http://linkedlifedata.com/resource/pubmed/chemical/Prostaglandin-Endoperoxide Synthases,
http://linkedlifedata.com/resource/pubmed/chemical/Ptgs1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Ptgs1 protein, rat,
http://linkedlifedata.com/resource/pubmed/chemical/Thiazoles
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BornemeierD ADA,
pubmed-author:ChaoJJ,
pubmed-author:ConnorD TDT,
pubmed-author:DoubledayRR,
pubmed-author:DyerR DRD,
pubmed-author:GilbertsenR BRB,
pubmed-author:GugliettaAA,
pubmed-author:RothB DBD,
pubmed-author:SchrierD JDJ,
pubmed-author:SercelA DAD,
pubmed-author:SongYY,
pubmed-author:SorensonR JRJ,
pubmed-author:UnangstP CPC
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pubmed:issnType |
Print
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pubmed:day |
8
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pubmed:volume |
42
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1151-60
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pubmed:dateRevised |
2005-11-17
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pubmed:meshHeading |
pubmed-meshheading:10197959-Administration, Oral,
pubmed-meshheading:10197959-Animals,
pubmed-meshheading:10197959-Anti-Inflammatory Agents, Non-Steroidal,
pubmed-meshheading:10197959-Carrageenan,
pubmed-meshheading:10197959-Cell Line,
pubmed-meshheading:10197959-Cyclooxygenase 1,
pubmed-meshheading:10197959-Cyclooxygenase 2,
pubmed-meshheading:10197959-Cyclooxygenase 2 Inhibitors,
pubmed-meshheading:10197959-Cyclooxygenase Inhibitors,
pubmed-meshheading:10197959-Dinoprostone,
pubmed-meshheading:10197959-Edema,
pubmed-meshheading:10197959-Gastric Mucosa,
pubmed-meshheading:10197959-Humans,
pubmed-meshheading:10197959-Hyperalgesia,
pubmed-meshheading:10197959-Isoenzymes,
pubmed-meshheading:10197959-Male,
pubmed-meshheading:10197959-Membrane Proteins,
pubmed-meshheading:10197959-Mice,
pubmed-meshheading:10197959-Oxazoles,
pubmed-meshheading:10197959-Phenols,
pubmed-meshheading:10197959-Prostaglandin-Endoperoxide Synthases,
pubmed-meshheading:10197959-Rats,
pubmed-meshheading:10197959-Rats, Sprague-Dawley,
pubmed-meshheading:10197959-Stomach Ulcer,
pubmed-meshheading:10197959-Structure-Activity Relationship,
pubmed-meshheading:10197959-Thiazoles
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pubmed:year |
1999
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pubmed:articleTitle |
Synthesis, structure-activity relationships, and in vivo evaluations of substituted di-tert-butylphenols as a novel class of potent, selective, and orally active cyclooxygenase-2 inhibitors. 1. Thiazolone and oxazolone series.
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pubmed:affiliation |
Departments of Chemistry, Biochemistry, and Immunopathology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA.
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pubmed:publicationType |
Journal Article
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