Source:http://linkedlifedata.com/resource/pubmed/id/20527969
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
13
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pubmed:dateCreated |
2010-7-1
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pubmed:abstractText |
A series of novel 2,4,6-trisubstitutedpyrimidine-5-carboxylic acid derivatives were designed and synthesized with the intent of producing a peroxisome proliferator-activated receptor gamma (PPARgamma) partial agonist for antidiabetic agents. A pharmacophore-driven approach of in-house screening identified compound 7, which led to the identification of compound 9 featuring a 2,4,6-trisubstituted pyrimidine-5-carboxylic acid core. Structure-activity relationship studies of 9 resulted in identifying 4,6-bisbenzylthio-2-methylthiopyrimidine-5-carboxylic acid (50) as the most attractive of all the screened compounds. The X-ray cocrystal structure of 50 bound on PPARgamma revealed that the key hydrogen bond interactions, which are not related to the activation function 2 (AF-2) site, are different from those of the full agonist. Compound 50 showed typical PPARgamma partial agonist properties in the PPARgamma-GAL4 functional assay and weaker differentiation of adipocytes in 3T3-L1 cells than observed with rosiglitazone. Furthermore, 50 displayed comparable antidiabetic efficacy with rosiglitazone in db/db mice, although its potency is 10-fold weaker than that of rosiglitazone.
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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/Carboxylic Acids,
http://linkedlifedata.com/resource/pubmed/chemical/Hypoglycemic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/PPAR gamma,
http://linkedlifedata.com/resource/pubmed/chemical/Pyrimidines,
http://linkedlifedata.com/resource/pubmed/chemical/Thiazolidinediones,
http://linkedlifedata.com/resource/pubmed/chemical/rosiglitazone
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1520-4804
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pubmed:author | |
pubmed:issnType |
Electronic
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pubmed:day |
8
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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 |
5012-24
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pubmed:meshHeading |
pubmed-meshheading:20527969-3T3-L1 Cells,
pubmed-meshheading:20527969-Animals,
pubmed-meshheading:20527969-Carboxylic Acids,
pubmed-meshheading:20527969-Crystallography, X-Ray,
pubmed-meshheading:20527969-Diabetes Mellitus, Type 2,
pubmed-meshheading:20527969-Hypoglycemic Agents,
pubmed-meshheading:20527969-Magnetic Resonance Spectroscopy,
pubmed-meshheading:20527969-Male,
pubmed-meshheading:20527969-Mass Spectrometry,
pubmed-meshheading:20527969-Mice,
pubmed-meshheading:20527969-PPAR gamma,
pubmed-meshheading:20527969-Pyrimidines,
pubmed-meshheading:20527969-Structure-Activity Relationship,
pubmed-meshheading:20527969-Thiazolidinediones
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pubmed:year |
2010
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pubmed:articleTitle |
Design, synthesis, and structure-activity relationship studies of novel 2,4,6-trisubstituted-5-pyrimidinecarboxylic acids as peroxisome proliferator-activated receptor gamma (PPARgamma) partial agonists with comparable antidiabetic efficacy to rosiglitazone.
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pubmed:affiliation |
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. shigeki.seto@mb.kyorin-pharm.co.jp
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pubmed:publicationType |
Journal Article
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