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Purity: ≥98%
GW3965 (GW-3965) HCl, the hydrochloride salt of GW3965, is a novel, potent, selective LXR (liver X receptor) agonist for hLXRα and hLXRβ with potential anti-inflammatory activity. 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 |
In vitro, GW3965 hydrochloride induces GBM cell death with increased effectiveness in tumor cells that express EGFRvIII. GW3965 hydrochloride decreases LDLR levels while upregulating the expression of the E3 ubiquitin ligase IDOL and the cholesterol transporter gene ABCA1[2]. Platelet aggregation and calcium mobilization induced by collagen or CRP are inhibited by LXR ligands. When platelets are activated with 1 μg/mL CRP, GW3965 hydrochloride (1 or 5 μM) exhibits a slight inhibitory effect on fibrinogen binding and P-selectin exposure. GW3965 hydrochloride (10 μM) and T0901317 (40 μM) at greater concentrations, however, decrease the amounts of fibrinogen and P-selectin on the platelet surface[3].
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| ln Vivo |
The CNS of non-pathological animals does not experience the elevation in neuroactive steroids that GW3965 hydrochloride causes in the spinal cord, cerebellum, and cerebral cortex of STZ-rats. When diabetic animals are treated with GW3965 hydrochloride, their spinal cords express more myelin basic protein and have higher levels of dihydroprogesterone[1]. In vivo, GW3965 hydrochloride (40 mg/kg, po) significantly increases GBM cell death by a factor of 25 and robustly promotes ABCA1 and decreases LDLR expression[2]. Additionally, it inhibits tumor growth by 59%. In vivo bleeding duration is prolonged and platelet thrombus development is regulated by GW3965 hydrochloride (2 mg/kg, IV)[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 |
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| References | |||
| Additional Infomation |
Targeting LDLR with the liver X receptor (LXR) agonist GW3965 caused inducible degrader of LDLR (IDOL)–mediated LDLR degradation and increased expression of the ABCA1 cholesterol efflux transporter, potently promoting tumor cell death in an in vivo GBM model. These results show that EGFRvIII can promote tumor survival through PI3K/SREBP-1–dependent upregulation of LDLR and suggest a role for LXR agonists in the treatment of GBM patients.[2]
A potent, selective, orally active LXR agonist was identified from focused libraries of tertiary amines. GW3965 (12) recruits the steroid receptor coactivator 1 to human LXRalpha in a cell-free ligand-sensing assay with an EC(50) of 125 nM and profiles as a full agonist on hLXRalpha and hLXRbeta in cell-based reporter gene assays with EC(50)'s of 190 and 30 nM, respectively. After oral dosing at 10 mg/kg to C57BL/6 mice, 12 increased expression of the reverse cholesterol transporter ABCA1 in the small intestine and peripheral macrophages and increased the plasma concentrations of HDL cholesterol by 30%. 12 will be a valuable chemical tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metabolism.[4] |
| Molecular Formula |
C33H31CLF3NO3.HCL
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| Molecular Weight |
618.51
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| Exact Mass |
617.171
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| Elemental Analysis |
C, 64.08; H, 5.22; Cl, 11.46; F, 9.21; N, 2.26; O, 7.76
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| CAS # |
405911-17-3
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| Related CAS # |
GW3965;405911-09-3
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| PubChem CID |
16078973
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| Appearance |
Typically exists as white to off-white solids at room temperature
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| LogP |
8.891
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
13
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| Heavy Atom Count |
42
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| Complexity |
753
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C(C(F)(F)F)=C([H])C([H])=C([H])C=1C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])OC1=C([H])C([H])=C([H])C(C([H])([H])C(=O)O[H])=C1[H])C([H])([H])C([H])(C1C([H])=C([H])C([H])=C([H])C=1[H])C1C([H])=C([H])C([H])=C([H])C=1[H].Cl[H]
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| InChi Key |
NMPUWJFHNOUNQU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H31ClF3NO3.ClH/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);1H
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| Chemical Name |
2-(3-(3-((2-chloro-3-(trifluoromethyl)benzyl)(2,2-diphenylethyl)amino)propoxy)phenyl)acetic acid hydrochloride
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| Synonyms |
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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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 (4.04 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 (4.04 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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 (4.04 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 10 mg/mL (16.17 mM) in Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6168 mL | 8.0839 mL | 16.1679 mL | |
| 5 mM | 0.3234 mL | 1.6168 mL | 3.2336 mL | |
| 10 mM | 0.1617 mL | 0.8084 mL | 1.6168 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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