Source:http://linkedlifedata.com/resource/pubmed/id/20686261
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
8
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| pubmed:dateCreated |
2010-8-5
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| pubmed:abstractText |
To find a novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor with anti-lipid peroxidative activity, a series of tetrahydroisoquinoline derivatives were synthesized and evaluated. A compound with a N-(4-hydroxy-2,3,5-trimethylphenyl)carbamoyl moiety at the 3-position and an octanoyl moiety at the 2-position (7) was demonstrated to show anti-foam cell formation activity stronger than and anti-lipid peroxidative activity comparable to those of Pactimibe, while it was hardly absorbed orally. To increase its bioavailability, the acyl chain at the 2-position was shortened and various polar or basic moieties were introduced at the 7-position of 7. Among the synthesized derivatives, (S)-7-dimethylamino-N-(4-hydroxy-2,3,5-trimethylphenyl)-2-isobutyryl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide hydrochloride (21) showed about 16-fold stronger anti-foam cell formation activity, 3-fold stronger hepatic ACAT inhibitory activity, similar anti-low density lipoprotein (LDL) oxidative activity and 2-fold more potent protective activity against macrophage cell death by oxidative stress in comparison with Pactimibe. Compound 21 was efficiently absorbed after oral administration at 10 mg/kg in rats and dogs and its C(max) values were higher than its IC(50) values for in vitro activities. In conclusion, a tetrahydroisoquinoline structure is a useful scaffold for designing a phenolic anti-oxidative ACAT inhibitor, and compound 21 is expected to effectively prevent atherosclerosis.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antioxidants,
http://linkedlifedata.com/resource/pubmed/chemical/Cholesterol,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Sterol O-Acyltransferase,
http://linkedlifedata.com/resource/pubmed/chemical/Tetrahydroisoquinolines
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| pubmed:status |
MEDLINE
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| pubmed:month |
Aug
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| pubmed:issn |
1347-5223
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| pubmed:author | |
| pubmed:issnType |
Electronic
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| pubmed:volume |
58
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| pubmed:owner |
NLM
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| pubmed:authorsComplete |
Y
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| pubmed:pagination |
1066-76
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| pubmed:dateRevised |
2011-3-8
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| pubmed:meshHeading |
pubmed-meshheading:20686261-Animals,
pubmed-meshheading:20686261-Antioxidants,
pubmed-meshheading:20686261-Cell Death,
pubmed-meshheading:20686261-Cholesterol,
pubmed-meshheading:20686261-Dogs,
pubmed-meshheading:20686261-Enzyme Inhibitors,
pubmed-meshheading:20686261-Esterification,
pubmed-meshheading:20686261-Lipid Peroxidation,
pubmed-meshheading:20686261-Macrophages,
pubmed-meshheading:20686261-Male,
pubmed-meshheading:20686261-Molecular Structure,
pubmed-meshheading:20686261-Oxidative Stress,
pubmed-meshheading:20686261-Rabbits,
pubmed-meshheading:20686261-Rats,
pubmed-meshheading:20686261-Rats, Sprague-Dawley,
pubmed-meshheading:20686261-Stereoisomerism,
pubmed-meshheading:20686261-Sterol O-Acyltransferase,
pubmed-meshheading:20686261-Structure-Activity Relationship,
pubmed-meshheading:20686261-Tetrahydroisoquinolines
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| pubmed:year |
2010
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| pubmed:articleTitle |
Novel tetrahydroisoquinoline derivatives with inhibitory activities against acyl-CoA: cholesterol acyltransferase and lipid peroxidation.
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| pubmed:affiliation |
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., 38 Nishinokyo Tsukinowa-cho, Nakagyo-ku, Kyoto, Japan.
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| pubmed:publicationType |
Journal Article
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