- 生物活性
SR3335 (ML 176) 是选择性的 RORα 反向激动剂，可直接结合 RORα，Ki为 220 nM。
- 靶点
Ki: 220 nM (RORα)
- 体外研究
SR3335 is a selective RORα partial inverse agonist. In a biochemical radioligand binding assay using [
3
H]25-hydroxycholesterol as a label it is clear that unlabeled SR3335 dose-dependently competes for binding to the RORα LBD. The K
i
is calculated as 220 nM using the Cheng-Prusoff equation. In a cell-based chimeric receptor Gal4 DNA-binding domain-NR ligand binding domain cotransfection assay, SR3335 significantly inhibits the constitutive transactivation activity of RORα (IC
50
=480 nM)(partial inverse agonist activity), but has no effect on the activity of LXRα and RORγ.
SR3335 suppresses the expression of endogenous RORα target genes in HepG2 cells that are involved in hepatic gluconeogenesis including glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK).
SR3335 also blocks IL-25 and IL-33-induced ILC2 proliferation and IL-13 production ex vivo.
- 体内研究
SR3335 displays reasonable exposure following an i.p. injection into mice. The ability of SR3335 is assessed to suppress gluconeogenesis using a diet induced obesity (DIO) mouse model where the mice where treated with 15 mg/kg b.i.d., i.p. for 6-days followed by a pyruvate tolerance test. SR3335 treated mice displays lower plasma glucose levels following the pyruvate challenge consistent with suppression of gluconeogenesis. Importantly, mice treated with SR3335 displayed no difference in body weight or food intake after 7-days of treatment with SR3335.
SR3335 (15 mg/kg/day; ip for 7 days) reduces rhinovirus (RV)-induced lung ILC2s in immature mice (RV infection of 6-day-old BALB/c mice).
医药
16629-19-9
722-92-9
293753-05-6
在氩气保护下，将4-(1-羟基-1-三氟甲基-2,2,2-三氟乙基)苯胺（A）（1.5M THF溶液，128μL，0.193mmol）溶于丙酮（643μL）中。随后，依次加入2,6-二甲基吡啶（29μL，0.251mmol）和2-噻吩磺酰氯（0.193mmol），反应在室温下进行。将反应混合物加热至80℃，持续反应1天。反应完成后，冷却至室温，用乙酸乙酯（EtOAc）和饱和碳酸氢钠（NaHCO3）溶液稀释。水相用乙酸乙酯萃取两次，合并有机相，经无水硫酸钠（Na2SO4）干燥，过滤并浓缩。粗产物通过硅胶柱色谱法纯化，使用己烷/乙酸乙酯（7/3）作为洗脱剂，得到目标产物N-[4-[2,2,2-三氟-1-羟基-1-(三氟甲基)乙基]苯基]-2-噻吩磺酰胺（SR3335），为白色粉末，产量48mg（收率62%）。该化合物的CAS号为2937-53-05-6，文献已知并可商购。
参考文献：
[1] Patent: WO2011/115892, 2011, A1. Location in patent: Page/Page column 6; 45; 46
