Liang Dongdong, Li Linhao, Lynch Caitlin, Diethelm-Varela Benjamin, Xia Menghang, Xue Fengtian, Wang Hongbing
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland 21201, United States.
National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland 20892-3375, United States.
ACS Med Chem Lett. 2019 Jun 12;10(7):1039-1044. doi: 10.1021/acsmedchemlett.9b00079. eCollection 2019 Jul 11.
The constitutive androstane receptor (CAR) is a xenobiotic sensor governing the transcription of genes involved in drug disposition, energy homeostasis, and cell proliferation. However, currently available human CAR (hCAR) agonists are nonselective, which commonly activate hCAR along with other nuclear receptors, especially the closely related human pregnane X receptor (hPXR). Using a well-known hCAR agonist CITCO as a template, we report our efforts in the discovery of a potent and highly selective hCAR agonist. Two of the new compounds of the series, and (DL5050), demonstrated excellent potency and selectivity for hCAR over hPXR. DL5050 preferentially induced the expression of CYP2B6 (target of hCAR) over CYP3A4 (target of hPXR) on both the mRNA and protein levels. The selective hCAR agonist DL5050 represents a valuable tool molecule to further define the biological functions of hCAR, and may also be used as a new lead in the discovery of hCAR agonists for various therapeutic applications.
组成型雄烷受体（CAR）是一种外源性物质传感器，可调控参与药物代谢、能量稳态和细胞增殖的基因转录。然而，目前可用的人CAR（hCAR）激动剂具有非选择性，通常会与其他核受体一起激活hCAR，尤其是密切相关的人孕烷X受体（hPXR）。以著名的hCAR激动剂CITCO为模板，我们报告了发现一种强效且高度选择性的hCAR激动剂的研究工作。该系列中的两种新化合物 和 （DL5050）对hCAR表现出优于hPXR的优异效力和选择性。DL5050在mRNA和蛋白质水平上均优先诱导CYP2B6（hCAR的靶标）的表达，而非CYP3A4（hPXR的靶标）的表达。选择性hCAR激动剂DL5050是进一步明确hCAR生物学功能的有价值工具分子，也可能用作发现用于各种治疗应用的hCAR激动剂的新先导物。
