Source:http://linkedlifedata.com/resource/pubmed/id/15943472
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
12
|
| pubmed:dateCreated |
2005-6-9
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| pubmed:abstractText |
The structure-activity relationship (SAR) of a novel hydrophobic binding interaction within a subsite of the influenza neuraminidase (NA) active site was characterized and optimized for a series of trisubstituted pyrrolidine inhibitors modified at the 4-position. Previously, potent inhibitors have targeted this subsite with hydrophilic substituents such as amines and guanidines. Inhibitor-bound crystal structures revealed that hydrophobic substituents with sp(2) hybridization could achieve optimal interactions by virtue of a low-energy binding conformation and favorable pi-stacking interactions with the residue Glu119. From a lead methyl ester, investigation of five-membered heteroaromatic substituents at C-4 produced a 3-pyrazolyl analogue that improved activity by making a targeted hydrogen bond with Trp178. The SAR of substituted vinyl substituents at C-4 produced a Z-propenyl analogue with improved activity over the lead methyl ester. The C-1 ethyl ester prodrugs of the substituted C-4 vinyl analogues gave compounds with excellent oral bioavailability (F > 60%) when dosed in rat.
|
| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
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| pubmed:month |
Jun
|
| pubmed:issn |
0022-2623
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| pubmed:author |
pubmed-author:CarrickRobert JRJ,
pubmed-author:GuYu-guiYG,
pubmed-author:KatiWarren MWM,
pubmed-author:Kempf-GroteAnitaA,
pubmed-author:KempfDale JDJ,
pubmed-author:KohlbrennerWilliam EWE,
pubmed-author:KruegerAllan CAC,
pubmed-author:LaverW GraemeWG,
pubmed-author:MadiganDarold LDL,
pubmed-author:MaringClarence JCJ,
pubmed-author:MarshKennan CKC,
pubmed-author:MollaAkhteruzzamanA,
pubmed-author:MontgomeryDebra ADA,
pubmed-author:ShamHing LHL,
pubmed-author:SteffyKevin RKR,
pubmed-author:StewartKent DKD,
pubmed-author:StollVincent SVS,
pubmed-author:SunMinghuaM,
pubmed-author:XuYiboY,
pubmed-author:ZhaoChenC
|
| pubmed:issnType |
Print
|
| pubmed:day |
16
|
| pubmed:volume |
48
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
3980-90
|
| pubmed:dateRevised |
2010-11-18
|
| pubmed:meshHeading |
pubmed-meshheading:15943472-Animals,
pubmed-meshheading:15943472-Binding Sites,
pubmed-meshheading:15943472-Biological Availability,
pubmed-meshheading:15943472-Crystallography, X-Ray,
pubmed-meshheading:15943472-Hydrophobic and Hydrophilic Interactions,
pubmed-meshheading:15943472-Influenza A virus,
pubmed-meshheading:15943472-Influenza B virus,
pubmed-meshheading:15943472-Models, Molecular,
pubmed-meshheading:15943472-Neuraminidase,
pubmed-meshheading:15943472-Pyrrolidines,
pubmed-meshheading:15943472-Rats,
pubmed-meshheading:15943472-Stereoisomerism,
pubmed-meshheading:15943472-Structure-Activity Relationship
|
| pubmed:year |
2005
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| pubmed:articleTitle |
Structure-based characterization and optimization of novel hydrophobic binding interactions in a series of pyrrolidine influenza neuraminidase inhibitors.
|
| pubmed:affiliation |
Department of Infectious Disease Research and Advanced Technology, Global Pharmaceutical R & D, Abbott Laboratories, Abbott Park, Illinois 60064, USA. clarence.maring@abbott.com
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| pubmed:publicationType |
Journal Article
|