5-Cyano-6-oxo-1,6-dihydro-pyrimidines as potent antagonists targeting exchange proteins directly activated by cAMP

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• 作者：Haijun Chen^a ; Tamara Tsalkova^a ; ^b ; Fang C. Mei^a ; ^b ; Yaohua Hu^a ; ^b ; Xiaodong Cheng^a ; ^b ; ^{xcheng@utmb.edu} ; Jia Zhou^a ; ^{jizhou@utmb.edu}
• 关键词：Pyrimidine analogues ; Exchange proteins directly activated by cAMP (Epac) ; Antagonists ; Structure&ndash ; activity relationship (SAR)
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2012
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 June, 2012
• 卷：22
• 期：12
• 页码：4038-4043
• 文件大小：745 K

摘要

Exchange proteins directly activated by cAMP (Epac) are a family of guanine nucleotide exchange factors that regulate a wide variety of intracellular processes in response to second messenger cAMP. To explore the structural determinants for Epac antagonist properties of high throughput screening (HTS) hit ESI-08, pyrimidine 1, a series of 5-cyano-6-oxo-1,6-dihydro-pyrimidine analogues have been synthesized and evaluated for their activities for Epac inhibition. Structure-activity relationship (SAR) analysis led to the identification of three more potent Epac antagonists (6b, 6g, and 6h). These inhibitors may serve as valuable pharmacological probes for further elucidation of the physiological functions and mechanisms of Epac regulation. Our SAR results and molecular docking studies have also revealed that further optimization of the moieties at the C-6 position of pyrimidine scaffold may allow us to discover more potent Epac-specific antagonists.