Faculty of Health Sciences, School of Pharmacy, University of Eastern Finland & Biocenter Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland.
Mol Pharm. 2011 Dec 5;8(6):2424-33. doi: 10.1021/mp2003658. Epub 2011 Nov 1.
The human constitutive androstane receptor (CAR, NR1I3) is one of the key regulators of xenobiotic and endobiotic metabolism. The unique properties of human CAR, such as the high constitutive activity and the complexity of signaling, as well as the lack of functional and predictive cell-based assays to study the properties of the receptor, have hindered the discovery of selective human CAR ligands. Here we report a novel human CAR inverse agonist, 1-[(2-methylbenzofuran-3-yl)methyl]-3-(thiophen-2-ylmethyl) urea (S07662), which suppresses human CAR activity, recruits the corepressor NCoR in cell-based assays, and attenuates the phenytoin- and 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime (CITCO)-induced expression of CYP2B6 mRNA in human primary hepatocytes. The properties of S07662 are also compared with those of known human CAR inverse agonists by using an array of different in vitro and in silico assays. The identified compound S07662 can be used as a chemical tool to study the biological functions of human CAR and also as a starting point for the development of new drugs for various conditions involving the receptor.
人组成型雄烷受体（CAR，NR1I3）是外源和内源性代谢物的关键调节剂之一。人 CAR 的独特性质，如高组成活性和信号转导的复杂性，以及缺乏用于研究受体性质的功能性和预测性基于细胞的测定法，阻碍了选择性人 CAR 配体的发现。在这里，我们报告了一种新型的人 CAR 反向激动剂，1-[(2-甲基苯并呋喃-3-基)甲基]-3-(噻吩-2-基甲基)脲（S07662），它可抑制人 CAR 活性，在基于细胞的测定中募集核心抑制因子 NCoR，并减弱苯妥英和 6-(4-氯苯基)咪唑[2,1-b][1,3]噻唑-5-甲酰基-O-(3,4-二氯苄基)肟（CITCO）诱导的人原代肝细胞中 CYP2B6 mRNA 的表达。还通过使用一系列不同的体外和计算测定法，比较了 S07662 的特性与已知的人 CAR 反向激动剂。所鉴定的化合物 S07662可用作研究人 CAR 生物学功能的化学工具，也可用作开发涉及受体的各种病症的新药的起点。
