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rdf:type |
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lifeskim:mentions |
umls-concept:C0033607,
umls-concept:C0072323,
umls-concept:C0205460,
umls-concept:C0205531,
umls-concept:C0220781,
umls-concept:C0220825,
umls-concept:C0226896,
umls-concept:C0318467,
umls-concept:C0442027,
umls-concept:C0935763,
umls-concept:C1527415,
umls-concept:C1707689,
umls-concept:C1883254,
umls-concept:C2603343,
umls-concept:C2936235
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pubmed:issue |
8
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pubmed:dateCreated |
2002-4-4
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pubmed:abstractText |
The structure-based design, chemical synthesis, and biological evaluation of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds are comprised of a peptidomimetic binding determinant and a Michael acceptor moiety, which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. The 2-pyridone-containing inhibitors typically display improved 3CP inhibition properties relative to related peptide-derived molecules along with more favorable antiviral properties. The cocrystal structure of one pyridone-derived 3CP inhibitor complexed with HRV-2 3CP is also described along with certain ab initio conformation analyses. Optimization of the 2-pyridone-containing compounds is shown to provide several highly active 3CP inhibitors (k(obs)/[I] > 500,00 M(-1) s(-1)) that function as potent antirhinoviral agents (EC(50) = <0.05 microM) against multiple virus serotypes in cell culture. One 2-pyridone-containing 3CP inhibitor is shown to be bioavailable in the dog after oral dosing (F = 48%).
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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 |
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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:BatugoMinerva RMR,
pubmed-author:BrownEdward LEL,
pubmed-author:ChenLijianL,
pubmed-author:DragovichPeter SPS,
pubmed-author:FerreRose AnnRA,
pubmed-author:FuhrmanShella ASA,
pubmed-author:GleesonJean-Paul RJP,
pubmed-author:GuzmanMark CMC,
pubmed-author:HendricksonThomas FTF,
pubmed-author:KosaMaha BMB,
pubmed-author:LeeCaroline ACA,
pubmed-author:MaldonadoFausto CFC,
pubmed-author:MatthewsDavid ADA,
pubmed-author:MeadorJames WJW3rd,
pubmed-author:PatickAmy KAK,
pubmed-author:PrinsThomas JTJ,
pubmed-author:SakataSylvie KSK,
pubmed-author:TuntlandToveT,
pubmed-author:WorlandStephen TST,
pubmed-author:XuN ZNZ,
pubmed-author:ZalmanLeora SLS,
pubmed-author:ZhouRuR
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pubmed:issnType |
Print
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pubmed:day |
11
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pubmed:volume |
45
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1607-23
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pubmed:dateRevised |
2007-10-11
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pubmed:meshHeading |
pubmed-meshheading:11931615-Administration, Oral,
pubmed-meshheading:11931615-Animals,
pubmed-meshheading:11931615-Antiviral Agents,
pubmed-meshheading:11931615-Biological Availability,
pubmed-meshheading:11931615-Crystallography, X-Ray,
pubmed-meshheading:11931615-Cysteine Endopeptidases,
pubmed-meshheading:11931615-Dogs,
pubmed-meshheading:11931615-Drug Stability,
pubmed-meshheading:11931615-Humans,
pubmed-meshheading:11931615-Ligands,
pubmed-meshheading:11931615-Microsomes, Liver,
pubmed-meshheading:11931615-Models, Molecular,
pubmed-meshheading:11931615-Molecular Mimicry,
pubmed-meshheading:11931615-Peptides,
pubmed-meshheading:11931615-Protease Inhibitors,
pubmed-meshheading:11931615-Protein Binding,
pubmed-meshheading:11931615-Pyridones,
pubmed-meshheading:11931615-Rhinovirus,
pubmed-meshheading:11931615-Structure-Activity Relationship,
pubmed-meshheading:11931615-Viral Proteins
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pubmed:year |
2002
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pubmed:articleTitle |
Structure-based design, synthesis, and biological evaluation of irreversible human rhinovirus 3C protease inhibitors. 6. Structure-activity studies of orally bioavailable, 2-pyridone-containing peptidomimetics.
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pubmed:affiliation |
Pfizer Global Research and Development-La Jolla/Agouron Pharmaceuticals, Inc., 10777 Science Center Drive, San Diego, California 92121-1111, USA. peter.dragvich@pfizer.com
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pubmed:publicationType |
Journal Article,
In Vitro
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