| pubmed-article:10956194 | rdf:type | pubmed:Citation | lld:pubmed |
| pubmed-article:10956194 | lifeskim:mentions | umls-concept:C0021246 | lld:lifeskim |
| pubmed-article:10956194 | lifeskim:mentions | umls-concept:C0002482 | lld:lifeskim |
| pubmed-article:10956194 | lifeskim:mentions | umls-concept:C0003211 | lld:lifeskim |
| pubmed-article:10956194 | lifeskim:mentions | umls-concept:C0014898 | lld:lifeskim |
| pubmed-article:10956194 | lifeskim:mentions | umls-concept:C1257954 | lld:lifeskim |
| pubmed-article:10956194 | lifeskim:mentions | umls-concept:C0243072 | lld:lifeskim |
| pubmed-article:10956194 | pubmed:issue | 15 | lld:pubmed |
| pubmed-article:10956194 | pubmed:dateCreated | 2000-9-5 | lld:pubmed |
| pubmed-article:10956194 | pubmed:abstractText | Recent studies from our laboratory have shown that derivatization of the carboxylate moiety in substrate analogue inhibitors, such as 5,8,11,14-eicosatetraynoic acid, and in nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin and meclofenamic acid, results in the generation of potent and selective cyclooxygenase-2 (COX-2) inhibitors (Kalgutkar et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 925-930). This paper summarizes details of the structure-activity studies involved in the transformation of the arylacetic acid NSAID, indomethacin, into a COX-2-selective inhibitor. Many of the structurally diverse indomethacin esters and amides inhibited purified human COX-2 with ICo5 values in the low-nanomolar range but did not inhibit ovine COX-1 activity at concentrations as high as 66 microM. Primary and secondary amide analogues of indomethacin were more potent as COX-2 inhibitors than the corresponding tertiary amides. Replacement of the 4-chlorobenzoyl group in indomethacin esters or amides with the 4-bromobenzyl functionality or hydrogen afforded inactive compounds. Likewise, exchanging the 2-methyl group on the indole ring in the ester and amide series with a hydrogen also generated inactive compounds. Inhibition kinetics revealed that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Conversion of indomethacin into ester and amide derivatives provides a facile strategy for generating highly selective COX-2 inhibitors and eliminating the gastrointestinal side effects of the parent compound. | lld:pubmed |
| pubmed-article:10956194 | pubmed:grant | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:10956194 | pubmed:language | eng | lld:pubmed |
| pubmed-article:10956194 | pubmed:journal | http://linkedlifedata.com/r... | lld:pubmed |
| pubmed-article:10956194 | pubmed:citationSubset | IM | lld:pubmed |
| pubmed-article:10956194 | pubmed:chemical | http://linkedlifedata.com/r... | lld:pubmed |
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| pubmed-article:10956194 | pubmed:status | MEDLINE | lld:pubmed |
| pubmed-article:10956194 | pubmed:month | Jul | lld:pubmed |
| pubmed-article:10956194 | pubmed:issn | 0022-2623 | lld:pubmed |
| pubmed-article:10956194 | pubmed:author | pubmed-author:MarnettL JLJ | lld:pubmed |
| pubmed-article:10956194 | pubmed:author | pubmed-author:RemmelR PRP | lld:pubmed |
| pubmed-article:10956194 | pubmed:author | pubmed-author:CrewsB CBC | lld:pubmed |
| pubmed-article:10956194 | pubmed:author | pubmed-author:KalgutkarA... | lld:pubmed |
| pubmed-article:10956194 | pubmed:author | pubmed-author:MarnettA BAB | lld:pubmed |
| pubmed-article:10956194 | pubmed:issnType | Print | lld:pubmed |
| pubmed-article:10956194 | pubmed:day | 27 | lld:pubmed |
| pubmed-article:10956194 | pubmed:volume | 43 | lld:pubmed |
| pubmed-article:10956194 | pubmed:owner | NLM | lld:pubmed |
| pubmed-article:10956194 | pubmed:authorsComplete | Y | lld:pubmed |
| pubmed-article:10956194 | pubmed:pagination | 2860-70 | lld:pubmed |
| pubmed-article:10956194 | pubmed:dateRevised | 2007-11-14 | lld:pubmed |
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| pubmed-article:10956194 | pubmed:meshHeading | pubmed-meshheading:10956194... | lld:pubmed |
| pubmed-article:10956194 | pubmed:year | 2000 | lld:pubmed |
| pubmed-article:10956194 | pubmed:articleTitle | Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. | lld:pubmed |
| pubmed-article:10956194 | pubmed:affiliation | Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA. | lld:pubmed |
| pubmed-article:10956194 | pubmed:publicationType | Journal Article | lld:pubmed |
| pubmed-article:10956194 | pubmed:publicationType | Research Support, U.S. Gov't, P.H.S. | lld:pubmed |
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