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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 |
2001-9-20
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pubmed:abstractText |
A novel series of arylcyclopropanecarboxyl guanidines was synthesized and evaluated for activity against the sodium hydrogen exchanger isoform-1 (NHE-1). In biological assays conducted in an AP1 cell line expressing the human NHE-1 isoform, the starting cyclopropane 3a (IC(50) = 3.5 microM) shows inhibitory activity comparable to cariporide (IC(50) = 3.4 microM). Structure-activity relationships are used to optimize the affinity of various acyl guanidines for NHE-1 by screening the effect of substituents at both aryl and cyclopropyl rings. It is demonstrated that introduction of appropriate hydrophobic groups at the phenyl ring and a gem-dimethyl group at the cyclopropane ring enhances the NHE-1 inhibitory activity by up to 3 orders of magnitude (compound 7f, IC(50) = 0.003 microM). In addition, the gem-dimethyl series of analogues seem to display improved oral bioavailability and longer plasma half-life in rats. Furthermore, the lead benzodihydrofuranyl analogue 1 (BMS-284640) shows over 380-fold increased NHE-1 inhibitory activity as well as improved selectivity for NHE-1 over NHE-2 compared to cariporide.
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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 |
Sep
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pubmed:issn |
0022-2623
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pubmed:author |
pubmed-author:AhmadSS,
pubmed-author:AtwalK SKS,
pubmed-author:ChenA YAY,
pubmed-author:ChenB CBC,
pubmed-author:DiMarcoJ DJD,
pubmed-author:DorsoC RCR,
pubmed-author:DoweykoL MLM,
pubmed-author:DuganWW,
pubmed-author:GavinB JBJ,
pubmed-author:GougoutasJ ZJZ,
pubmed-author:GrazierNN,
pubmed-author:KirbyMM,
pubmed-author:LanS JSJ,
pubmed-author:NgoAA,
pubmed-author:SerafinoRR,
pubmed-author:WuS CSC,
pubmed-author:YostK JKJ
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pubmed:issnType |
Print
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pubmed:day |
27
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pubmed:volume |
44
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3302-10
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pubmed:dateRevised |
2006-11-15
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pubmed:meshHeading |
pubmed-meshheading:11563929-Administration, Oral,
pubmed-meshheading:11563929-Animals,
pubmed-meshheading:11563929-Biological Availability,
pubmed-meshheading:11563929-Cation Transport Proteins,
pubmed-meshheading:11563929-Cell Line,
pubmed-meshheading:11563929-Cricetinae,
pubmed-meshheading:11563929-Crystallography, X-Ray,
pubmed-meshheading:11563929-Cyclopropanes,
pubmed-meshheading:11563929-Guanidines,
pubmed-meshheading:11563929-Humans,
pubmed-meshheading:11563929-Membrane Proteins,
pubmed-meshheading:11563929-Protein Isoforms,
pubmed-meshheading:11563929-Rats,
pubmed-meshheading:11563929-Sodium-Hydrogen Antiporter,
pubmed-meshheading:11563929-Stereoisomerism,
pubmed-meshheading:11563929-Structure-Activity Relationship
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pubmed:year |
2001
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pubmed:articleTitle |
Arylcyclopropanecarboxyl guanidines as novel, potent, and selective inhibitors of the sodium hydrogen exchanger isoform-1.
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pubmed:affiliation |
Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, NJ 08543, USA. saleem.ahmad@bms.com
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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