Document Detail

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.
MedLine Citation:
PMID:  20527969     Owner:  NLM     Status:  MEDLINE    
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.
Shigeki Seto; Kyoko Okada; Koichi Kiyota; Shigeki Isogai; Maki Iwago; Takehiro Shinozaki; Yoshiaki Kitamura; Yasushi Kohno; Koji Murakami
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  53     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-01     Completed Date:  2010-07-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5012-24     Citation Subset:  IM    
Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399-1, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
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MeSH Terms
3T3-L1 Cells
Carboxylic Acids / chemical synthesis,  chemistry,  pharmacology*
Crystallography, X-Ray
Diabetes Mellitus, Type 2 / drug therapy
Hypoglycemic Agents / chemical synthesis,  chemistry,  pharmacology*
Magnetic Resonance Spectroscopy
Mass Spectrometry
PPAR gamma / agonists*
Pyrimidines / chemical synthesis,  chemistry,  pharmacology*
Structure-Activity Relationship
Thiazolidinediones / chemistry,  pharmacology*
Reg. No./Substance:
0/Carboxylic Acids; 0/Hypoglycemic Agents; 0/PPAR gamma; 0/Pyrimidines; 0/Thiazolidinediones; 122320-73-4/rosiglitazone

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