Ligand-Based Design, Synthesis, and Biological Evaluation of 2-Aminopyrimidines, a Novel Series of Receptor for Advanced Glycation End Products (RAGE) Inhibitors

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• 作者：Young Taek Han ; Gyeong-In Choi ; Dohyun Son ; Nam-Jung Kim ; Hwayoung Yun ; Sujin Lee ; Dong Jo Chang ; Hyun-Seok Hong ; Hee Kim ; Hee-Jin Ha ; Young-Ho Kim ; Hyun-Ju Park ; Jeewoo Lee ; Young-Ger Suh
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 8, 2012
• 年：2012
• 卷：55
• 期：21
• 页码：9120-9135
• 全文大小：548K
• 年卷期：v.55,no.21(November 8, 2012)
• ISSN：1520-4804

文摘

Using the approach of ligand-based drug design, we discovered a novel series of 4,6-disubstituted 2-aminopyrimidines as RAGE inhibitors. In transgenic mouse models of AD, one of the 4,6-bis(4-chlorophenyl)pyrimidine analogs, 59, significantly lowered the concentration of toxic soluble A尾 in the brain and improved cognitive function. SPR analysis confirmed the direct binding of 59 with RAGE, which should contribute to its biological activities via inhibition of the RAGE鈥揂尾 interaction. We also predicted the binding mode of the 4,6-bis(4-chlorophenyl)pyrimidine analogs to the RAGE V-domain through flexible docking study.