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发现 2-(4-甲基呋喃-2(5H)-亚基)丙二腈和噻吩并[3,2-b]噻吩-2-羧酸衍生物作为 G 蛋白偶联受体 35（GPR35）激动剂。

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.

机构信息

Biochemical Technologies, Science and Technology Division, Corning Inc., Corning, New York 14831, United States.

出版信息

J Med Chem. 2011 Oct 27;54(20):7385-96. doi: 10.1021/jm200999f. Epub 2011 Oct 4.

DOI:10.1021/jm200999f
PMID:21950657
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3198121/
Abstract

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 EC(50) 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.

摘要

在 HT-29 天然细胞系中使用动态质量重分布 (DMR) 测定法进行筛选，鉴定出两种新型的化学化合物系列，即 2-(4-甲基呋喃-2(5H)-亚基)丙二腈和噻吩并[3,2-b]噻吩-2-羧酸衍生物，它们是 GPR35 激动剂。在这些化合物中，2-(3-氰基-5-(3,4-二氯苯基)-4,5-二甲基呋喃-2(5H)-亚基)丙二腈 (YE120) 和 6-溴-3-甲基噻吩并[3,2-b]噻吩-2-羧酸 (YE210) 被发现是两种最有效的 GPR35 激动剂，EC(50)分别为 32.5±1.7 nM 和 63.7±4.1 nM。这两种激动剂的效力均优于已知的 GPR35 激动剂扎普司特。DMR 拮抗剂测定、干扰 RNA 敲低 GPR35、受体内化测定和 Tango β-arrestin 易位测定证实，这些配体的激动剂活性是特异性针对 GPR35 的。本研究提供了新的化学系列，为进一步研究 GPR35 的生物学和药理学提供了起点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/af7db1ba7aef/jm-2011-00999f_0008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/af7db1ba7aef/jm-2011-00999f_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/a5a6031f15f2/jm-2011-00999f_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/e935d7970094/jm-2011-00999f_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/9f183bd9872e/jm-2011-00999f_0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/18efbe1ad23b/jm-2011-00999f_0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/f90df6e6e463/jm-2011-00999f_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/84699d79833b/jm-2011-00999f_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/91202c16b216/jm-2011-00999f_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/21551f5a5c10/jm-2011-00999f_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/ec36a4fc9ae3/jm-2011-00999f_0005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6d91/3198121/af7db1ba7aef/jm-2011-00999f_0008.jpg

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