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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
8
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pubmed:dateCreated |
2010-4-15
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pubmed:abstractText |
We have previously reported compound 2 as a inhibitor of acyl-coenzyme A:cholesterol O-acyltransferase (ACAT) and up-regulator of the low density lipoprotein receptor (LDL-R) expression. In this study we focused on compound 2, a unique LDL-R up-regulator, and describe the discovery of a novel class of up-regulators of LDL-R. Replacement the methylene urea linker in compound 2 with an acylsulfonamide linker kept a potent LDL-R up-regulatory activity, and subsequent optimization work gave compound 39 as a highly potent LDL-R up-regulator (39; EC(25) = 0.047 microM). Compound 39 showed no ACAT inhibitory activity even at 1 microM. The sodium salts of compound 39 reduced plasma total and LDL cholesterol levels in a dose-dependent manner in an experimental animal model of hyperlipidemia. Moreover, we revealed in this study using RNA interference that autosomal recessive hypercholesterolemia (ARH), an adaptor protein of LDL-R, is essential for compound 39 up-regulation of LDL-R expression.
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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/Adaptor Proteins, Signal Transducing,
http://linkedlifedata.com/resource/pubmed/chemical/Cholesterol, LDL,
http://linkedlifedata.com/resource/pubmed/chemical/Hypolipidemic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/LDLRAP1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, LDL,
http://linkedlifedata.com/resource/pubmed/chemical/Sterol O-Acyltransferase,
http://linkedlifedata.com/resource/pubmed/chemical/Sulfonic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Triglycerides
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pubmed:status |
MEDLINE
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pubmed:month |
Apr
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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 |
22
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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 |
3284-95
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pubmed:dateRevised |
2010-11-18
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pubmed:meshHeading |
pubmed-meshheading:20356098-Adaptor Proteins, Signal Transducing,
pubmed-meshheading:20356098-Animals,
pubmed-meshheading:20356098-Biological Availability,
pubmed-meshheading:20356098-Cell Line, Tumor,
pubmed-meshheading:20356098-Cholesterol, LDL,
pubmed-meshheading:20356098-Cricetinae,
pubmed-meshheading:20356098-Humans,
pubmed-meshheading:20356098-Hyperlipidemias,
pubmed-meshheading:20356098-Hypolipidemic Agents,
pubmed-meshheading:20356098-Male,
pubmed-meshheading:20356098-Pyrimidines,
pubmed-meshheading:20356098-RNA Interference,
pubmed-meshheading:20356098-Receptors, LDL,
pubmed-meshheading:20356098-Sterol O-Acyltransferase,
pubmed-meshheading:20356098-Structure-Activity Relationship,
pubmed-meshheading:20356098-Sulfonic Acids,
pubmed-meshheading:20356098-Triglycerides,
pubmed-meshheading:20356098-Up-Regulation
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pubmed:year |
2010
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pubmed:articleTitle |
A novel class of antihyperlipidemic agents with low density lipoprotein receptor up-regulation via the adaptor protein autosomal recessive hypercholesterolemia.
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pubmed:affiliation |
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan. shigehiro-asano@ds-pharma.co.jp
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pubmed:publicationType |
Journal Article
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