Source:http://linkedlifedata.com/resource/pubmed/id/11428926
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
14
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| pubmed:dateCreated |
2001-6-28
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| pubmed:abstractText |
Due largely to the emergence of multi-drug-resistant HIV strains, the development of new HIV protease inhibitors remains a high priority for the pharmaceutical industry. Toward this end, we previously identified a 4-hydroxy-5,6-dihydropyrone lead compound (CI-1029, 1) which possesses excellent activity against the protease enzyme, good antiviral efficacy in cellular assays, and promising bioavailability in several animal species. The search for a suitable back-up candidate centered on the replacement of the aniline moiety at C-6 with an appropriately substituted heterocyle. In general, this series of heterocyclic inhibitors displayed good activity (in both enzymatic and cellular tests) and low cellular toxicity; furthermore, several analogues exhibited improved pharmacokinetic parameters in animal models. The compound with the best combination of high potency, low toxicity, and favorable bioavailabilty was (S)-3-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (13-(S)). This thiophene derivative also exhibited excellent antiviral efficacy against mutant HIV protease and resistant HIV strains. For these reasons, compound 13-(S) was chosen for further preclinical evaluation.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
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| pubmed:month |
Jul
|
| pubmed:issn |
0022-2623
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| pubmed:author |
pubmed-author:BrodfuehrerJJ,
pubmed-author:DomagalaJJ,
pubmed-author:GajcyHH,
pubmed-author:GracheckS JSJ,
pubmed-author:HagenS ESE,
pubmed-author:HollenPP,
pubmed-author:HuppKK,
pubmed-author:LovdahlMM,
pubmed-author:LunneyE AEA,
pubmed-author:NouhanCC,
pubmed-author:PavlovskyAA,
pubmed-author:SaundersJJ,
pubmed-author:TaitB DBD,
pubmed-author:UrumovAA,
pubmed-author:VanderRoestSS,
pubmed-author:WiseEE,
pubmed-author:ZeikusEE,
pubmed-author:ZeikusGG
|
| pubmed:issnType |
Print
|
| pubmed:day |
5
|
| pubmed:volume |
44
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| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
2319-32
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| pubmed:dateRevised |
2004-11-17
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| pubmed:meshHeading |
pubmed-meshheading:11428926-Animals,
pubmed-meshheading:11428926-Biological Availability,
pubmed-meshheading:11428926-Cell Line,
pubmed-meshheading:11428926-Chromatography, High Pressure Liquid,
pubmed-meshheading:11428926-Dogs,
pubmed-meshheading:11428926-Drug Evaluation, Preclinical,
pubmed-meshheading:11428926-Drug Resistance, Microbial,
pubmed-meshheading:11428926-HIV,
pubmed-meshheading:11428926-HIV Protease,
pubmed-meshheading:11428926-HIV Protease Inhibitors,
pubmed-meshheading:11428926-HIV-1,
pubmed-meshheading:11428926-Humans,
pubmed-meshheading:11428926-Lymphocytes,
pubmed-meshheading:11428926-Mice,
pubmed-meshheading:11428926-Mutation,
pubmed-meshheading:11428926-Pyrones,
pubmed-meshheading:11428926-Rats,
pubmed-meshheading:11428926-Stereoisomerism,
pubmed-meshheading:11428926-Structure-Activity Relationship,
pubmed-meshheading:11428926-Sulfides
|
| pubmed:year |
2001
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| pubmed:articleTitle |
4-Hydroxy-5,6-dihydropyrones as inhibitors of HIV protease: the effect of heterocyclic substituents at C-6 on antiviral potency and pharmacokinetic parameters.
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| pubmed:affiliation |
Department of Chemistry, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. Susan.hagen@pfizer.com
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| pubmed:publicationType |
Journal Article
|