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
| Autor: | Yasushi Kohno, Koji Murakami, Shigeki Seto, Maki Iwago, Kyoko Okada, Shigeki Isogai, Takehiro Shinozaki, Yoshiaki Kitamura, Koichi Kiyota |
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| Rok vydání: | 2010 |
| Předmět: |
Agonist
Male medicine.medical_specialty Magnetic Resonance Spectroscopy medicine.drug_class Carboxylic Acids Peroxisome proliferator-activated receptor Pharmacology Crystallography X-Ray Partial agonist Mass Spectrometry Rosiglitazone Mice Structure-Activity Relationship Internal medicine 3T3-L1 Cells Drug Discovery medicine Structure–activity relationship Animals Hypoglycemic Agents Receptor chemistry.chemical_classification Peroxisome PPAR gamma Endocrinology Pyrimidines chemistry Diabetes Mellitus Type 2 Molecular Medicine Thiazolidinediones Peroxisome proliferator-activated receptor alpha medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 53(13) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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