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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
9
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pubmed:dateCreated |
2010-5-6
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pubmed:abstractText |
Deletion of phenylalanine residue 508 (DeltaF508) in the cystic fibrosis (CF) transmembrane conductance regulator protein (CFTR) is a major cause of CF. Small molecule "correctors" of defective DeltaF508-CFTR cellular processing hold promise for CF therapy. We previously identified and characterized bithiazole CF corrector 1 and s-cis-locked bithiazole 2. Herein, we report the regiodivergent synthesis of Ngamma and Nbeta isomers of thiazole-tethered pyrazoles with improved hydrophilicity compared to bithiazoles. We synthesized a focused library of 54 pyrazolylthiazoles 3, which included examples of both regioisomers 4 and 5. The thiazole-tethered pyrazoles allowed incorporation of property-modulating functionality on the pyrazole ring (ester, acid, and amide) while retaining DeltaF508-CFTR corrector activity (EC(50)) of under 1 microM. The most active pyrazolylthiazole (14h) has an experimentally determined log P of 4.1, which is 1.2 log units lower than bithiazole CF corrector 1.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-10720935,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-11124952,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-11423120,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-12007216,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-12832418,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-1380723,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-16750628,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-16774229,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-16870453,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-18394886,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-18788728,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20373765-3543048
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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 |
May
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pubmed:issn |
1520-4804
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
13
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pubmed:volume |
53
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3772-81
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pubmed:dateRevised |
2011-9-26
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pubmed:meshHeading |
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pubmed:year |
2010
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pubmed:articleTitle |
Pyrazolylthiazole as DeltaF508-cystic fibrosis transmembrane conductance regulator correctors with improved hydrophilicity compared to bithiazoles.
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pubmed:affiliation |
Department of Chemistry, University of California, Davis, Davis, California 95616, USA.
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pubmed:publicationType |
Journal Article,
Research Support, U.S. Gov't, Non-P.H.S.,
Research Support, Non-U.S. Gov't,
Research Support, N.I.H., Extramural
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