新型含硅视黄酸受体相关孤儿受体反向激动剂的研发
Development of novel silicon-containing inverse agonists of retinoic acid receptor-related orphan receptors.
作者信息
Toyama Hirozumi, Nakamura Masaharu, Nakamura Masahiko, Matsumoto Yotaro, Nakagomi Madoka, Hashimoto Yuichi
机构信息
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
出版信息
Bioorg Med Chem. 2014 Mar 15;22(6):1948-59. doi: 10.1016/j.bmc.2014.01.023. Epub 2014 Feb 8.
Retinoic acid receptor (RAR)-related orphan receptors (RORs) regulate a variety of physiological processes, including hepatic gluconeogenesis, lipid metabolism, circadian rhythm and immune function. The RAR agonist: all-trans retinoic acid was reported to be an RORβ inverse agonist, but no information is available regarding ROR activity of its synthetic analogue Am580. Therefore, we screened Am580 and some related tetramethyltetrahydronaphthalene derivatives and carried out structural development studies, including substitution of carbon atoms with silicon, with the aim of creating a potent ROR transcriptional inhibitor. The phenyl amide disila compound 22 showed the most potent ROR-inhibitory activity among the compounds examined. Its activity towards RORα, RORβ and RORγ was increased compared to that of Am580. The IC₅₀ values for RORα, RORβ and RORγ are 1.3, >10 and 4.5 μM, respectively.
维甲酸受体（RAR）相关孤儿受体（RORs）调节多种生理过程，包括肝脏糖异生、脂质代谢、昼夜节律和免疫功能。据报道，RAR激动剂全反式维甲酸是一种RORβ反向激动剂，但关于其合成类似物Am580的ROR活性尚无相关信息。因此，我们筛选了Am580和一些相关的四甲基四氢萘衍生物，并进行了结构开发研究，包括用硅取代碳原子，旨在创建一种有效的ROR转录抑制剂。在所研究的化合物中，苯基酰胺二硅化合物22表现出最强的ROR抑制活性。与Am580相比，其对RORα、RORβ和RORγ的活性有所增强。RORα、RORβ和RORγ的IC₅₀值分别为1.3、>10和4.5 μM。
Zotero 插件