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Purity: ≥98%
GW3965 (GW-3965) is a novel, potent, selective LXR (liver X receptor) agonist for hLXRα and hLXRβ with anti-inflammatory effects. In cell-based reporter gene assays, GW3965 plays as a full agonist on hLXRα and hLXRβ with EC50 of 190 and 30 nM, respectively. GW3965 suppresses the production of pro-inflammatory cytokines by murine mast cells. GW3965 improves recovery from mild repetitive traumatic brain injury in mice partly through apolipoprotein E. GW3965 reduces tissue factor production and inflammatory responses in human islets in vitro. GW3965 dose-dependently regulates lps-mediated liver injury and modulates posttranscriptional TNF-alpha production and p38 mitogen-activated protein kinase activation in liver macrophages.
| Targets |
hLXRα (EC50 = 190 nM); hLXRβ(EC50 = 30 nM)[4]
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| ln Vitro |
GW3965 increases the effectiveness of tumor cells expressing EGFRvIII and drives GBM cell death in vitro. GW3965 decreases LDLR levels and increases the expression of the cholesterol transporter gene ABCA1 and E3 ubiquitin ligase IDOL [2]. Platelet aggregation and calcium mobilization stimulated by collagen or CRP are inhibited by LXR ligands. When platelets were stimulated with 1 μg/mL CRP, GW3965 (1 or 5 μM) had mild inhibitory effects on fibrinogen binding and P-selectin exposure. However, the levels of fibrinogen and P-selectin on the platelet surface decrease when GW3965 (10 μM) or T0901317 (40 μM) at greater doses are applied [3].
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| ln Vivo |
In the spinal cord, cerebellum, and cerebral cortex of STZ rats, but not in the central nervous system of non-pathological animals, GW3965 causes an increase in neuroactive hormones. In the spinal cord of diabetic rats, GW3965 therapy increases dihydropregnanolone and is linked to an increase in the expression of myelin basic protein [1]. GW3965 (40 mg/kg, orally) increases GBM cell death in vivo by a factor of 25 and significantly increases ABCA1 expression and decreases LDLR expression [2]. It also inhibits tumor growth by 59%. Intravenous GW3965 (2 mg/kg) prolongs bleeding duration and modifies platelet thrombosis in vivo [3].
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| Enzyme Assay |
Tertiary amine 3 was identified from a high-throughput screen of the GlaxoSmithKline compound file using a cell-free ligand-sensing assay (LiSA) for human LXRα. The LXRα LiSA measures the ligand-dependent recruitment of a 24 amino acid fragment of the steroid receptor coactivator 1 (SRC1) to the ligand-binding domain of the receptor[4].
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| Cell Assay |
A total of 6 × 103 cells were seeded into 6-well plates in 5% FBS for 24 hours, then changed to 1% LPDS medium and treated with GW3965 in time course manner. Cells were washed once using PBS; then total RNA was extracted using TRIzol reagent according to its protocol (Invitrogen). Next, 800 ng RNA was complementarily synthesized to cDNA and amplified using real-time PCR (Bio-Rad), and its values were normalized against the internal control gene 36B4 (RPLP0) for each replicate. The primers used were as follows: ABCA1 forward: 5′-AACAGTTTGTGGCCCTTTTG-3′, reverse: 5′-AGTTCCAGGCTGGGGTACTT-3′; IDOL forward: 5′-CGAGGACTGCCTCAACCA-3′, reverse: 5′-TGCAGTCCAAAATAGTCAACTTCT-3′; 36B4 forward: 5′-AATGGCAGCATCTACAAC-CC-3′, reverse: 5′-TCGTTTGTACCCGTTGATGA-3′[2].
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| Animal Protocol |
Age and weight matched male C57BL/6J mice were housed 5 mice /cage at 21°C and 50% relative humidity with a 12-hr light:dark cycle. Mice were fed a standard rodent chow (PMI Feeds, 5001) and were provided food and water ad libitum. C57BL/6J mice were dosed by oral gavage twice daily with GW3965A at 10mg/kg or vehicle (0.5% Methyl Cellulose) for 3, 7 or 14 days. Blood was collected under isofluorane anesthesia via cardiac puncture. Serum lipid measurements were obtained with an automated chemistry analyzer. Changes in ABCA1 mRNA expression were measured using the ABI7700 Sequence Detector. RNA was isolated from GW3965 tissues from treated animals using Trizol reagent. Fold changes are based upon the cycle threshold values obtained with vehicle treated control samples. All procedures performed were in compliance with the Animal Welfare ACT and U.S. Department of Agriculture regulation and were approved by the GlaxoSmithKline Institutional Animal Care and Use Committee[4].
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| References |
[1]. Mitro, Nico., et al. LXR and TSPO as new therapeutic targets to increase the levels of neuroactive steroids in the central nervous system of diabetic animals. Neurochemistry International (2012), 60(6), 616-621.
[2]. Guo, Deliang., et al. An LXR Agonist Promotes Glioblastoma Cell Death through Inhibition of an EGFR/AKT/SREBP-1/LDLR-Dependent Pathway. Cancer Discovery (2011), 1(5), 442-456. [3]. Spyridon, Michael., et al. LXR as a novel antithrombotic target. Blood (2011), 117(21), 5751-5761. [4]. [4]. Collins JL, et al. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem. 2002 May 9;45(10):1963-6. |
| Additional Infomation |
GW 3965 is a diarylmethane.
GW-3965 is a liver X receptor ligand. 3-(3-(N-(2-Chloro-3-trifluoromethylbenzyl)(2,2-diphenylethyl)amino)propoxy)phenylacetic acid has been reported in Pestalotiopsis neglecta with data available. |
| Molecular Formula |
C33H31CLF3NO3
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|---|---|
| Molecular Weight |
582.05
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| Exact Mass |
581.194
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| CAS # |
405911-09-3
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| Related CAS # |
GW3965 hydrochloride;405911-17-3
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| PubChem CID |
447905
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
672.4±55.0 °C at 760 mmHg
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| Flash Point |
360.5±31.5 °C
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| Vapour Pressure |
0.0±2.2 mmHg at 25°C
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| Index of Refraction |
1.583
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| LogP |
8.2
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
41
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| Complexity |
753
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=C(C(F)(F)F)C=CC=C1CN(CC(C2=CC=CC=C2)C3=CC=CC=C3)CCCOC4=CC(CC(O)=O)=CC=C4
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| InChi Key |
NAXSRXHZFIBFMI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H31ClF3NO3/c34-32-27(15-8-17-30(32)33(35,36)37)22-38(18-9-19-41-28-16-7-10-24(20-28)21-31(39)40)23-29(25-11-3-1-4-12-25)26-13-5-2-6-14-26/h1-8,10-17,20,29H,9,18-19,21-23H2,(H,39,40)
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| Chemical Name |
2-[3-[3-[[2-chloro-3-(trifluoromethyl)phenyl]methyl-(2,2-diphenylethyl)amino]propoxy]phenyl]acetic acid
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| Synonyms |
GW-3965; GW3965; UNII-6JI5YOG7RC; 6JI5YOG7RC; GW-3965A; GW 3965
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7181 mL | 8.5903 mL | 17.1807 mL | |
| 5 mM | 0.3436 mL | 1.7181 mL | 3.4361 mL | |
| 10 mM | 0.1718 mL | 0.8590 mL | 1.7181 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.
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