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Purity: ≥98%
SR3335 (also known as ML-176) is a novel and selective RORα inverse agonist with a Ki of 220 nM. SR3335 directly binds to RORα, but not other RORs, and functions as a selective partial inverse agonist of RORα in cell-based assays. Furthermore, SR3335 suppresses the expression of endogenous RORα target genes in HepG2 involved in hepatic gluconeogenesis including glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Pharmacokinetic studies indicate that SR3335 displays reasonable exposure following an ip injection into mice. We assess the ability of SR3335 to suppress gluconeogenesis in vivo using a diet-induced obesity (DIO) mouse model where the mice where treated with 15 mg/kg b.i.d., ip for 6 days followed by a pyruvate tolerance test. SR3335-treated mice displayed lower plasma glucose levels following the pyruvate challenge consistent with suppression of gluconeogenesis. Thus, SR3335 was identified as the first selective synthetic RORα inverse agonist, and this compound can be utilized as a chemical tool to probe the function of this receptor both in vitro and in vivo. Additionally, the data suggests that RORα inverse agonists may hold utility for suppression of elevated hepatic glucose production in type 2 diabetics.
| ln Vitro |
SR3335 is a partial inverse agonist of RORα that is selective. It was clear that unlabeled SR3335 competed with RORα LBD in a dose-dependent manner in a biochemical factor ligand binding test with [3H]25-pillow as the binding label, with a Ki computed using the Cheng-Prusoff equation of 220 nM. While SR3335 had no influence on the activities of LXRα and RORγ, it considerably decreased the constitutive transactivation activity of RORα (IC50= 480 nM) (partial inverse agonist activity) in the cell co-transfection experiment of the chimeric receptor Gal4 DNA binding domain-NR ligand binding domain [1]. In HepG2 cells, endogenous RORα target genes involved in hepatic gluconeogenesis, such as phosphoenolpyruvyl acetonitrile (PEPCK) and potential-6-phosphatase (G6Pase), are inhibited by SR3335 [2]. Moreover, IL-25 and IL-33-induced ILC2 proliferation and IL-13 production can be externally burst by SR3335 [3].
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| ln Vivo |
After intraperitoneal injection, SR3335 exhibited a reasonable level of exposure in mice. Using the diet-induced exercise (DIO) animal paradigm, which involves treating mice with 15 mg/kg bid, ip for 6 days before testing them for pyruvate tolerance, the efficacy of SR3335 to suppress gluconeogenesis was assessed. Following pyruvate challenge, animals treated with SR3335 exhibited reduced transcript levels, which is consistent with transcriptional gluconeogenesis. Significantly, SR3335 (15 mg/kg/day; intraperitoneally for 7 days) therapy decreased rhinovirus (RV) infection in immature mice (6-day-old BALB/c mice) with lung ILC2s caused by RV[3].
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| References |
[1]. Kumar N, et al. Identification of SR3335 (ML-176): a synthetic RORα selective inverse agonist. ACS Chem Biol. 2011 Mar 18;6(3):218-22.
[2]. Rajput C, et al. RORα-dependent type 2 innate lymphoid cells are required and sufficient for mucous metaplasia in immature mice. Am J Physiol Lung Cell Mol Physiol. 2017;312(6):L983-L993 |
| Molecular Formula |
C13H9F6NO3S2
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| Molecular Weight |
405.33
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| CAS # |
293753-05-6
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| SMILES |
O=S(C1=CC=CS1)(NC2=CC=C(C(C(F)(F)F)(O)C(F)(F)F)C=C2)=O
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.17 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.17 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4671 mL | 12.3356 mL | 24.6713 mL | |
| 5 mM | 0.4934 mL | 2.4671 mL | 4.9343 mL | |
| 10 mM | 0.2467 mL | 1.2336 mL | 2.4671 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Identification of a selective RORα synthetic ligand, SR3335.ACS Chem Biol.2011 Mar 18;6(3):218-22. |
SR3335 is a selective RORα partial inverse agonist. |
SR3335 suppresses the expression of RORα target genes.
SR3335 suppresses gluconeogenesisin vivo.ACS Chem Biol.2011 Mar 18;6(3):218-22. |
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