5-Cyano-6-oxo-1,6-dihydro-pyrimidines as potent antagonists targeting exchange proteins directly activated by cAMP.
5-Cyano-6-oxo-1,6-dihydro-pyrimidines as potent antagonists targeting exchange proteins directly activated by cAMP.
复制标题
DOI：
10.1016/j.bmcl.2012.04.082
复制
发表时间：
2012-06-15
影响因子：
2.7
通讯作者：
Zhou, Jia
中科院分区：
文献类型：
--
作者：
Chen, Haijun;Tsalkova, Tamara;Mei, Fang C.;Hu, Yaohua;Cheng, Xiaodong;Zhou, Jia
关键词：
由cAMP直接激活的交换蛋白（Epac）是响应于第二信使cAMP调节多种细胞内过程的鸟嘌呤核苷酸交换因子家族。为了探索高通量筛选（HTS）的Epac拮抗剂性质的结构决定因素，通过ESI-08，嘧啶1，合成了一系列5-氰基-6-氧代-1，6-二氢-嘧啶类似物，并评价了它们对Epac抑制的活性。构效关系（SAR）分析导致三个更有效的Epac拮抗剂（6 b，6 g和6 h）的鉴定。这些抑制剂可能作为有价值的药理学探针，进一步阐明的生理功能和机制的Epac的调节。我们的SAR结果和分子对接研究也表明，在嘧啶支架的C-6位的部分的进一步优化，可以让我们发现更有效的Epac特异性拮抗剂。
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.
登录
查看更多内容
影响因子：
11.2
作者：
Lissitzky, Jean-Claude;Parriaux, Danielle;Verrando, Patrick
通讯作者：
Verrando, Patrick
影响因子：
56.9
作者：
Kawasaki, H;Springett, GM;Graybiel, AM
通讯作者：
Graybiel, AM
影响因子：
4.8
作者：
Li, Sheng;Tsalkova, Tamara;Cheng, Xiaodong
通讯作者：
Cheng, Xiaodong
影响因子：
20.1
作者：
Metrich, Melanie;Lucas, Alexandre;Lezoualc'h, Frank
通讯作者：
Lezoualc'h, Frank
DOI：
10.1152/ajpheart.00937.2007
发表时间：
2008-03-01
影响因子：
4.8
作者：
Adamson, R. H.;Ly, J. C.;Curry, F. E.
通讯作者：
Curry, F. E.