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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
20
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pubmed:dateCreated |
2005-9-29
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pubmed:abstractText |
Using a focused screening approach, acyl ureas have been discovered as a new class of inhibitors of human liver glycogen phosphorylase (hlGPa). The X-ray structure of screening hit 1 (IC50 = 2 microM) in a complex with rabbit muscle glycogen phosphorylase b reveals that 1 binds at the AMP site, the main allosteric effector site of the dimeric enzyme. A first cycle of chemical optimization supported by X-ray structural data yielded derivative 21, which inhibited hlGPa with an IC50 of 23 +/- 1 nM, but showed only moderate cellular activity in isolated rat hepatocytes (IC50 = 6.2 microM). Further optimization was guided by (i) a 3D pharmacophore model that was derived from a training set of 24 compounds and revealed the key chemical features for the biological activity and (ii) the 1.9 angstroms crystal structure of 21 in complex with hlGPa. A second set of compounds was synthesized and led to 42 with improved cellular activity (hlGPa IC50 = 53 +/- 1 nM; hepatocyte IC50 = 380 nM). Administration of 42 to anaesthetized Wistar rats caused a significant reduction of the glucagon-induced hyperglycemic peak. These findings are consistent with the inhibition of hepatic glycogenolysis and support the use of acyl ureas for the treatment of type 2 diabetes.
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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 |
Oct
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:BrachvogelVolkerV,
pubmed-author:BurgerHans-JörgHJ,
pubmed-author:DefossaElisabethE,
pubmed-author:HerlingAndreas WAW,
pubmed-author:KadereitDieterD,
pubmed-author:KlabundeThomasT,
pubmed-author:KosmopoulouMagda NMN,
pubmed-author:OikonomakosNikos GNG,
pubmed-author:SarubbiEdoardoE,
pubmed-author:SchönafingerKarlK,
pubmed-author:SchmollDieterD,
pubmed-author:WendtK UlrichKU,
pubmed-author:von RoedernErichE
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pubmed:issnType |
Print
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pubmed:day |
6
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pubmed:volume |
48
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
6178-93
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:16190745-Adenosine Monophosphate,
pubmed-meshheading:16190745-Allosteric Site,
pubmed-meshheading:16190745-Animals,
pubmed-meshheading:16190745-Binding Sites,
pubmed-meshheading:16190745-Crystallography, X-Ray,
pubmed-meshheading:16190745-Diabetes Mellitus, Type 2,
pubmed-meshheading:16190745-Glycogen Phosphorylase, Liver Form,
pubmed-meshheading:16190745-Glycogen Phosphorylase, Muscle Form,
pubmed-meshheading:16190745-Hepatocytes,
pubmed-meshheading:16190745-Humans,
pubmed-meshheading:16190745-Models, Molecular,
pubmed-meshheading:16190745-Quantitative Structure-Activity Relationship,
pubmed-meshheading:16190745-Rabbits,
pubmed-meshheading:16190745-Rats,
pubmed-meshheading:16190745-Urea
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pubmed:year |
2005
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pubmed:articleTitle |
Acyl ureas as human liver glycogen phosphorylase inhibitors for the treatment of type 2 diabetes.
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pubmed:affiliation |
Sanofi-Aventis Deutschland GmbH, Scientific and Medical Affairs, D-65926 Frankfurt am Main, Germany.
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pubmed:publicationType |
Journal Article,
In Vitro,
Research Support, Non-U.S. Gov't
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