- 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
合成路线 1（1. 合成：293753-05-6）
产率：62%
合成条件：With 2,6-dimethylpyridine In acetone at 80℃; for 24 h; Inert atmosphere
实验步骤：在氩气下，向4-（1-羟基-1-三氟甲基-2,2,2-三氟乙基）苯胺（A）（1.5M在THF中，128μL，0.193mmol）在丙酮（643μL）中的溶液中依次进行 在室温下加入2,6-二甲基吡啶（29μL，0.251mmol）和相应的芳基磺酰氯（0.193mmol）。 将混合物在80℃加热1天，然后冷却至室温并用乙酸乙酯（EtOAc）和饱和NaHCO 3溶液稀释。 将水相用EtOAc萃取两次，并将合并的有机相经Na 2 SO 4干燥，过滤并蒸发。 通过硅胶柱色谱法纯化粗残余物，得到磺酰胺B.按照方法A制备SR3335，并用己烷/ EtOAc（7/3）纯化，得到48mg（62％），为白色粉末。 该化合物在文献中已知并可商购（CAS 2937-53-05-6）。
参考文献：
- [1] Patent: WO2011/115892, 2011, A1. Location in patent: Page/Page column 6; 45; 46
