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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
4
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pubmed:dateCreated |
2010-2-19
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pubmed:databankReference |
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pubmed:abstractText |
In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.
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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/Azepines,
http://linkedlifedata.com/resource/pubmed/chemical/Cholesterol, LDL,
http://linkedlifedata.com/resource/pubmed/chemical/Hypolipidemic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Indoles,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Cytoplasmic and Nuclear,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, LDL,
http://linkedlifedata.com/resource/pubmed/chemical/Triglycerides,
http://linkedlifedata.com/resource/pubmed/chemical/farnesoid X-activated receptor
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:Borges-MarcucciLisaL,
pubmed-author:CommonsThomasT,
pubmed-author:CrawleyMatthew LML,
pubmed-author:EtaJulius EJE,
pubmed-author:EvansMark JMJ,
pubmed-author:FeingoldIreneI,
pubmed-author:GreenDaniel MDM,
pubmed-author:HarnishDouglas CDC,
pubmed-author:HumWah-TungWT,
pubmed-author:KimCallain YCY,
pubmed-author:LaiKehdihK,
pubmed-author:LundquistJoseph TJT,
pubmed-author:MahaneyPaige EPE,
pubmed-author:MehlmannJohn FJF,
pubmed-author:PatelVikramV,
pubmed-author:PhippsKristin MKM,
pubmed-author:UnwallaRayomand JRJ,
pubmed-author:WrobelJay EJE,
pubmed-author:XuWeixinW
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pubmed:issnType |
Electronic
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pubmed:day |
25
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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 |
1774-87
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:20095622-Animals,
pubmed-meshheading:20095622-Azepines,
pubmed-meshheading:20095622-Biological Availability,
pubmed-meshheading:20095622-Cell Line,
pubmed-meshheading:20095622-Cholesterol, LDL,
pubmed-meshheading:20095622-Female,
pubmed-meshheading:20095622-Humans,
pubmed-meshheading:20095622-Hypolipidemic Agents,
pubmed-meshheading:20095622-Indoles,
pubmed-meshheading:20095622-Macaca mulatta,
pubmed-meshheading:20095622-Male,
pubmed-meshheading:20095622-Mice,
pubmed-meshheading:20095622-Mice, Knockout,
pubmed-meshheading:20095622-Microsomes, Liver,
pubmed-meshheading:20095622-Models, Molecular,
pubmed-meshheading:20095622-Rats,
pubmed-meshheading:20095622-Rats, Sprague-Dawley,
pubmed-meshheading:20095622-Receptors, Cytoplasmic and Nuclear,
pubmed-meshheading:20095622-Receptors, LDL,
pubmed-meshheading:20095622-Solubility,
pubmed-meshheading:20095622-Structure-Activity Relationship,
pubmed-meshheading:20095622-Triglycerides
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pubmed:year |
2010
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pubmed:articleTitle |
Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: beneficial modulation of lipids in primates.
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pubmed:affiliation |
Department of Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville, Pennsylvania 19426, USA. lundquj@wyeth.com
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pubmed:publicationType |
Journal Article
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