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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
17
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pubmed:dateCreated |
2004-8-5
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pubmed:abstractText |
Hepatic blockade of glucocorticoid receptors (GR) suppresses glucose production and thus decreases circulating glucose levels, but systemic glucocorticoid antagonism can produce adrenal insufficiency and other undesirable side effects. These hepatic and systemic responses might be dissected, leading to liver-selective pharmacology, when a GR antagonist is linked to a bile acid in an appropriate manner. Bile acid conjugation can be accomplished with a minimal loss of binding affinity for GR. The resultant conjugates remain potent in cell-based functional assays. A novel in vivo assay has been developed to simultaneously evaluate both hepatic and systemic GR blockade; this assay has been used to optimize the nature and site of the linker functionality, as well as the choice of the GR antagonist and the bile acid. This optimization led to the identification of A-348441, which reduces glucose levels and improves lipid profiles in an animal model of diabetes.
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pubmed:commentsCorrections |
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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 |
Aug
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:ApelqvistTheresaT,
pubmed-author:BarkhemTomasT,
pubmed-author:FärnegårdhMathiasM,
pubmed-author:FungStevenS,
pubmed-author:Goos-NilssonAnnikaA,
pubmed-author:GrynfarbMarlenaM,
pubmed-author:HöglundMarieM,
pubmed-author:HagbergLarsL,
pubmed-author:HutchinsCharlesC,
pubmed-author:JacobsonPeer BPB,
pubmed-author:JaeHwan-SooHS,
pubmed-author:JakobClarissaC,
pubmed-author:KauppiBjörnB,
pubmed-author:KoehlerKonradK,
pubmed-author:KymPhilip RPR,
pubmed-author:LaiChunqiuC,
pubmed-author:LinkJames TJT,
pubmed-author:NguyenPhongP,
pubmed-author:OhmanLarsL,
pubmed-author:OsterlundMarieM,
pubmed-author:RhonnstadPatrikP,
pubmed-author:SandbergJohnnyJ,
pubmed-author:TuNoahN,
pubmed-author:WangJiahongJ,
pubmed-author:WilcoxDeniseD,
pubmed-author:von GeldernThomas WTW
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pubmed:copyrightInfo |
Copyright 2004 American Chemical Society
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pubmed:issnType |
Print
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pubmed:day |
12
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pubmed:volume |
47
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
4213-30
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pubmed:dateRevised |
2005-11-17
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pubmed:meshHeading |
pubmed-meshheading:15293993-Animals,
pubmed-meshheading:15293993-Bile Acids and Salts,
pubmed-meshheading:15293993-Binding Sites,
pubmed-meshheading:15293993-Bridged Compounds,
pubmed-meshheading:15293993-CHO Cells,
pubmed-meshheading:15293993-Cells, Cultured,
pubmed-meshheading:15293993-Computer Simulation,
pubmed-meshheading:15293993-Cricetinae,
pubmed-meshheading:15293993-Diabetes Mellitus, Experimental,
pubmed-meshheading:15293993-Diabetes Mellitus, Type 2,
pubmed-meshheading:15293993-Glucose,
pubmed-meshheading:15293993-Humans,
pubmed-meshheading:15293993-Hypoglycemic Agents,
pubmed-meshheading:15293993-Hypothalamo-Hypophyseal System,
pubmed-meshheading:15293993-Liver,
pubmed-meshheading:15293993-Male,
pubmed-meshheading:15293993-Mice,
pubmed-meshheading:15293993-Models, Molecular,
pubmed-meshheading:15293993-Pituitary-Adrenal System,
pubmed-meshheading:15293993-Rats,
pubmed-meshheading:15293993-Rats, Sprague-Dawley,
pubmed-meshheading:15293993-Receptors, Glucocorticoid,
pubmed-meshheading:15293993-Structure-Activity Relationship
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pubmed:year |
2004
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pubmed:articleTitle |
Liver-selective glucocorticoid antagonists: a novel treatment for type 2 diabetes.
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pubmed:affiliation |
Metabolic Disease Research and Structural Biology Departments, Global Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois 60064, UDA. thomas.vongeldern@abbott.com
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pubmed:publicationType |
Journal Article
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