Design, Synthesis, and Structure−Activity Relationship Studies of Novel 2,4,6-Trisubstituted-5-pyrimidinecarboxylic Acids as Peroxisome Proliferator-Activated Receptor γ (PPARγ) Partia

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• 作者：Shigeki Seto ; Kyoko Okada ; Koichi Kiyota ; Shigeki Isogai ; Maki Iwago ; Takehiro Shinozaki ; Yoshiaki Kitamura ; Yasushi Kohno ; Koji Murakami
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：July 8, 2010
• 年：2010
• 卷：53
• 期：13
• 页码：5012-5024
• 全文大小：1071K
• 年卷期：v.53,no.13(July 8, 2010)
• ISSN：1520-4804

文摘

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 γ (PPARγ) 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 PPARγ 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 PPARγ partial agonist properties in the PPARγ-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.