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rdf:type |
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lifeskim:mentions |
umls-concept:C0205460,
umls-concept:C0205531,
umls-concept:C0220781,
umls-concept:C0226896,
umls-concept:C0243192,
umls-concept:C0441655,
umls-concept:C0442027,
umls-concept:C0470187,
umls-concept:C1527415,
umls-concept:C1707689,
umls-concept:C1825292,
umls-concept:C1883254
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pubmed:issue |
5
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pubmed:dateCreated |
2011-3-3
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pubmed:abstractText |
G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic ?-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC(50) = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC(50) = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.
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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 |
Mar
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pubmed:issn |
1520-4804
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pubmed:author |
pubmed-author:FukatsuKohjiK,
pubmed-author:FunamiMiyukiM,
pubmed-author:HaradaMasatakaM,
pubmed-author:KanzakiNaoyukiN,
pubmed-author:KitamuraShujiS,
pubmed-author:KobayashiMakotoM,
pubmed-author:MomoseYuY,
pubmed-author:NegoroNobuyukiN,
pubmed-author:SantouTakashiT,
pubmed-author:SasakiShinobuS,
pubmed-author:SuzukiMasamiM,
pubmed-author:SuzukiNobuhiroN,
pubmed-author:TadaNorioN,
pubmed-author:TanakaToshimasaT,
pubmed-author:TanakaYasuhiroY,
pubmed-author:TsujihataYoshiyukiY,
pubmed-author:YamamotoYoshioY,
pubmed-author:YasumaTsuneoT
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pubmed:issnType |
Electronic
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pubmed:day |
10
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pubmed:volume |
54
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1365-78
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pubmed:meshHeading |
pubmed-meshheading:21319751-Administration, Oral,
pubmed-meshheading:21319751-Animals,
pubmed-meshheading:21319751-Biphenyl Compounds,
pubmed-meshheading:21319751-Blood Glucose,
pubmed-meshheading:21319751-CHO Cells,
pubmed-meshheading:21319751-Cricetinae,
pubmed-meshheading:21319751-Cricetulus,
pubmed-meshheading:21319751-Diabetes Mellitus, Experimental,
pubmed-meshheading:21319751-Drug Design,
pubmed-meshheading:21319751-Glucose Tolerance Test,
pubmed-meshheading:21319751-Humans,
pubmed-meshheading:21319751-Hypoglycemic Agents,
pubmed-meshheading:21319751-Male,
pubmed-meshheading:21319751-Phenylpropionates,
pubmed-meshheading:21319751-Rats,
pubmed-meshheading:21319751-Rats, Sprague-Dawley,
pubmed-meshheading:21319751-Receptors, G-Protein-Coupled,
pubmed-meshheading:21319751-Stereoisomerism,
pubmed-meshheading:21319751-Structure-Activity Relationship
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pubmed:year |
2011
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pubmed:articleTitle |
Design, synthesis, and biological activity of potent and orally available G protein-coupled receptor 40 agonists.
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pubmed:affiliation |
Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Sasaki_Shinobu@takeda.co.jp
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pubmed:publicationType |
Journal Article
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