Discovery of 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3,2-b]thiophene-2-carboxylic acid derivatives as G protein-coupled receptor 35 (GPR35) agonists.
Discovery of 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3,2-b]thiophene-2-carboxylic acid derivatives as G protein-coupled receptor 35 (GPR35) agonists.
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DOI：
10.1021/jm200999f
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发表时间：
2011-10-27
影响因子：
7.3
通讯作者：
Fang, Ye
中科院分区：
文献类型：
--
作者：
Deng, Huayun;Hu, Haibei;He, Mingqian;Hu, Jieyu;Niu, Weijun;Ferrie, Ann M.;Fang, Ye
在原生细胞系HT-29中进行动态质量重分布（DMR）筛选，鉴定出两个新的化合物系列，2-（4-甲基呋喃-2(5H)-乙基）丙二腈和噻吩-2-羧酸衍生物，作为GPR35的激动剂。其中，2-（3-氰基-5-（3,4-二氯苯基）-4,5-二甲基呋喃-2(5H)-乙基）丙二腈（YE120）和6-溴-3-甲基噻吩-2-羧酸（YE210）是两种最有效的GPR35激动剂，EC50分别为32.5±1.7 nM和63.7±4.1 nM。两种激动剂均表现出比已知的GPR35激动剂zaprinast更好的效力。DMR拮抗剂试验、干扰RNA敲低GPR35、受体内化试验和Tango β-阻滞蛋白易位试验证实，这些配体的激动剂活性是GPR35特异性的。本研究为进一步研究GPR35的生物学和药理学提供了新的化学序列起点。
Screening with dynamic mass redistribution (DMR) assays in a native cell line HT-29 led to identification of two novel series of chemical compounds, 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3,2-b]thiophene-2-carboxylic acid derivatives, as GPR35 agonists. Of these, 2-(3-cyano-5-(3,4-dichlorophenyl)-4,5-dimethylfuran-2(5H)-ylidene)malononitrile (YE120) and 6-bromo-3-methylthieno[3,2-b]thiophene-2-carboxylic acid (YE210) were found to be the two most potent GPR35 agonists with an EC50 of 32.5 ± 1.7 nM and 63.7 ± 4.1 nM, respectively. Both agonists exhibited better potency than that of zaprinast, a known GPR35 agonist. DMR antagonist assays, knockdown of GPR35 with interference RNA, receptor internalization assays, and Tango β-arrestin translocation assays confirmed that the agonist activity of these ligands is specific to GPR35. The present study provides novel chemical series as a starting point for further investigations of GPR35 biology and pharmacology.
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影响因子：
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作者：
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DOI：
10.1016/j.bbrc.2010.01.076
发表时间：
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影响因子：
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作者：
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