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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
13
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pubmed:dateCreated |
2006-6-22
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pubmed:abstractText |
Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.
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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 |
http://linkedlifedata.com/resource/pubmed/chemical/Benzimidazoles,
http://linkedlifedata.com/resource/pubmed/chemical/Oligopeptides,
http://linkedlifedata.com/resource/pubmed/chemical/PTPN1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Phosphotyrosine,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatase...,
http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatases,
http://linkedlifedata.com/resource/pubmed/chemical/Proto-Oncogene Proteins c-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Insulin,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfonamides,
http://linkedlifedata.com/resource/pubmed/chemical/Thiazoles
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pubmed:status |
MEDLINE
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pubmed:month |
Jun
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AlaPaul JPJ,
pubmed-author:BowerMichaelM,
pubmed-author:BurnTimothy CTC,
pubmed-author:CombsAndrew PAP,
pubmed-author:CrawleyMatthew LML,
pubmed-author:EllisDawnD,
pubmed-author:EmmThomasT,
pubmed-author:GlassBrianB,
pubmed-author:GonnevilleLucieL,
pubmed-author:HollisGregoryG,
pubmed-author:LiYanlongY,
pubmed-author:LiuPhillip C CPC,
pubmed-author:McLaughlinErinE,
pubmed-author:MetcalfBrianB,
pubmed-author:ModiDilipD,
pubmed-author:PolamPadmajaP,
pubmed-author:ReidBrian MBM,
pubmed-author:RuparMarkM,
pubmed-author:SparksRichard BRB,
pubmed-author:TakvorianAmyA,
pubmed-author:TaylorNancyN,
pubmed-author:WassermanZeldaZ,
pubmed-author:WeiMinM,
pubmed-author:WynnRichardR,
pubmed-author:YeleswaramSwamyS,
pubmed-author:YueEddy WEW,
pubmed-author:ZhuWenyuW
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pubmed:issnType |
Print
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pubmed:day |
29
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pubmed:volume |
49
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3774-89
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:16789735-Benzimidazoles,
pubmed-meshheading:16789735-Cell Line,
pubmed-meshheading:16789735-Crystallography, X-Ray,
pubmed-meshheading:16789735-Humans,
pubmed-meshheading:16789735-Models, Molecular,
pubmed-meshheading:16789735-Molecular Mimicry,
pubmed-meshheading:16789735-Molecular Structure,
pubmed-meshheading:16789735-Oligopeptides,
pubmed-meshheading:16789735-Phosphorylation,
pubmed-meshheading:16789735-Phosphotyrosine,
pubmed-meshheading:16789735-Protein Tyrosine Phosphatase, Non-Receptor Type 1,
pubmed-meshheading:16789735-Protein Tyrosine Phosphatases,
pubmed-meshheading:16789735-Proto-Oncogene Proteins c-akt,
pubmed-meshheading:16789735-Receptor, Insulin,
pubmed-meshheading:16789735-Stereoisomerism,
pubmed-meshheading:16789735-Structure-Activity Relationship,
pubmed-meshheading:16789735-Sulfonamides,
pubmed-meshheading:16789735-Thiazoles
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pubmed:year |
2006
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pubmed:articleTitle |
Potent benzimidazole sulfonamide protein tyrosine phosphatase 1B inhibitors containing the heterocyclic (S)-isothiazolidinone phosphotyrosine mimetic.
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pubmed:affiliation |
Incyte Corporation, Discovery Chemistry, Applied Technology, and Drug Metabolism, Experimental Station, Route 141 and Henry Clay Road, Wilmington, Delaware 19880, USA. acombs@incyte.com
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pubmed:publicationType |
Journal Article
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