REV-ERBΑ/Β激动剂(SR9011HYDROCHLORIDE) | 2070014-94-5

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 中文名称: REV-ERBΑ/Β激动剂(SR9011HYDROCHLORIDE)
• 英文名称: SR9011 hydrochloride
• 英文别名: 3-[[(4-chlorophenyl)methyl-[(5-nitrothiophen-2-yl)methyl]amino]methyl]-N-pentylpyrrolidine-1-carboxamide;hydrochloride
• CAS: 2070014-94-5
• 化学式: C23H32Cl2N4O3S
• 分子量: 515.5
• InChiKey: ADTZBBQVEUEODS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.96
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  110
• 氢给体数：
  2
• 氢受体数：
  5

制备方法与用途

生物活性

SR9011 hydrochloride 是一种 REV-ERBα/β 激动剂，作用于 REV-ERBα 和 REV-ERBβ，IC50s 分别为 790 nM 和 560 nM。

靶点

IC50: 790 nM (Rev-ErbBα), 560 nM (Rev-ErbBβ)

体外研究

SR9011 dose-dependently increases the REV-ERB-dependent repressor activity assessed in HEK293 cells expressing a chimeric Gal4 DNA Binding Domain (DBD) - REV-ERB ligand binding domain (LBD) α or β and a Gal4-responsive luciferase reporter (REV-ERBα IC ₅₀ =790 nM, REV-ERBβ IC ₅₀ =560 nM). SR9011 potently and efficaciously suppresses transcription in a cotransfection assay using full-length REV-ERBα along with a luciferase reporter driven by the Bmal1 promoter (SR9011 IC ₅₀ =620 nM). SR9011 suppresses the expression ofBMAL1 mRNA in HepG2 cells in a REV-ERBα/β -dependent manner SR9011 suppresses proliferation of the breast cancer cell lines regardless of their ER or HER2 status. SR9011 appears to pause the cell cycle of the breast cancer cells prior to M phase. Cyclin A ( CCNA2 ) is identified as a direct target gene of REV-ERB suggesting that suppression of expression of this cyclin by SR9011 may mediate the cell cycle arrest. Treatment with SR9011 results in an increase in cells in the G ₀ /G ₁ phase and a decrease of cells in S and G ₂ /M phase suggesting that activation of REV-ERB may be resulting in decreased transition from G ₁ to S phase and/or from S to G ₂ /M phase.

体内研究

SR9011 displays reasonable plasma exposure, thus, the expression of REV-ERB responsive genes is examined in the liver of mice treated with various doses of SR9011 for 6-days. The plasminogen activator inhibitor type 1 gene ( Serpine1 ) is a REV-ERB target gene and displays dose-dependent suppression of expression in response to SR9011. The cholesterol 7α-hydroxylase ( Cyp7a1 ) and sterol response element binding protein ( Srepf1 ) genes have also been shown to be responsive to REV-ERB and are dose-dependently suppressed with increasing amounts of SR9011. After 12 days in D:D conditions mice are injected with a single dose of SR9011 or vehicle at CT6 (peak expression of Rev-erbα ). Vehicle injection causes no disruption in circadian locomotor activity. However, administration of a single dose of SR9011 results in loss of locomotor activity during the subject dark phase. Normal activity returns the next circadian cycle, consistent with clearance of the drugs in less than 24h. The SR9011-dependent decrease in wheel running behavior in the mice under constant darkness conditions is dose-dependent and that the potency (ED ₅₀ =56 mg/kg) is similar to the potency of SR9011-mediated suppression of a REV-ERB responsive gene, Srebf1 , in vivo (ED ₅₀ =67mg/kg).