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Purity: ≥98%
GW-870086 is a novel and potent glucocorticoid receptor agonist that has anti-inflammatory properties, and thus can be potentially usef for the treatment of asthma and atopic dermatitis.. It acts as a glucocorticoid receptor agonist with a pIC50 of 10.1 in A549 cells expressing NF-κB.
| Targets |
Glucocorticoid receptor (GR) – GW870086 binds to the GR with a pIC₅₀ of 8.2 ± 0.02 in a fluorescence displacement assay using isolated GR.
The compound shows minimal activity (<5 pIC₅₀) at estrogen, progesterone, mineralocorticoid, and androgen receptors.[1] |
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| ln Vitro |
The glucocorticoid receptor agonist GW-870086 has a pIC50 of 10.1 and suppresses the NFkB reporter gene; however, it has no effect on the MMTV reporter gene in A549 cells, nor on the progesterone or estrogen receptors. little or nonexistent action at androgen or mineralocorticoid receptors. GW-870086 (1 pM-1 μM) suppresses IL-1-induced L-6 release in MG63 osteosarcoma cells and dose-dependently TNF-α in A549 epithelial cancer cells (pIC50s, 9.6, 10.2)[1]. GW-870086 (GW870086X; 10-100 nM) dramatically boosts the release of fibronectin. GW-870086, however, does not enhance cellular myofibrillar protein or affect MMP2 secretion [2].
GW870086 potently represses TNF-α-induced IL-6 release in A549 epithelial cells (pIC₅₀ 10.1 ± 0.02) and IL-1-induced IL-6 release in MG63 osteosarcoma cells (pIC₅₀ 10.6 ± 0.02), comparable to fluticasone propionate (FP). In contrast, GW870086 shows minimal transactivation activity on an MMTV-driven luciferase reporter in A549 cells (≤2% maximal response) and acts as a partial agonist/antagonist in MG63 and NIH-3T3 cells. Gene expression profiling in A549 cells reveals that GW870086 represses TNF-induced genes (e.g., LTB, PTGS2) and down-regulates certain GR target genes (e.g., Cyp24a1) similarly to dexamethasone, but has little to no effect on other GR-upregulated genes (e.g., SGK). In 16HBE respiratory epithelial cells, GW870086 inhibits TNF-α-induced IL-8 release and increases transepithelial electrical resistance, but fails to protect cells from elastase-mediated detachment, unlike FP. |
| ln Vivo |
In a murine irritant-induced contact dermatitis model (oxazolone challenge), topical GW870086 reduces ear swelling in a dose-dependent manner, comparable to FP.
In a murine ovalbumin-induced allergic airway inflammation model, intratracheal GW870086 (10, 30, 100 μg) dose-dependently inhibits airway hyperresponsiveness to 5-HT and reduces inflammatory cell influx into bronchoalveolar lavage fluid, with efficacy similar to FP but slightly lower potency. |
| Enzyme Assay |
A fluorescence displacement assay was used to measure binding to the glucocorticoid receptor. Isolated GR was incubated with a fluorescently labeled glucocorticoid tracer and increasing concentrations of GW870086. Displacement of the tracer was measured to determine binding affinity (pIC₅₀).
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| Cell Assay |
For NF-κB transrepression assays, A549 cells stably transfected with an NF-κB-driven secreted placental alkaline phosphatase reporter were seeded in 384-well plates, pretreated with compound for 1 h, then stimulated with TNF-α. Alkaline phosphatase activity was measured 15 h later.
For MMTV transactivation assays, A549 or MG63 cells stably transfected with an MMTV-LTR-driven Renilla luciferase reporter were seeded in 96-well plates, treated with compound for 16 h, and luciferase activity was measured after adding coelenterazine. For cytokine release assays, cells were seeded in 96-well plates, pretreated with compound for 1 h, stimulated with TNF-α or IL-1, and supernatants were collected 16 h later for IL-6 measurement by immunoassay. For gene expression analysis by Q-PCR, A549 cells were treated with compound for 1 h, stimulated with TNF-α for 5 h, then RNA was extracted and target gene expression was quantified. For 16HBE epithelial cell functional assays, cells were treated with compound, then stimulated with TNF-α for IL-8 ELISA, or grown on Transwell membranes to measure transepithelial resistance after 24 h, or challenged with neutrophil elastase to assess monolayer integrity. |
| Animal Protocol |
For the delayed-type hypersensitivity model, mice were sensitized by topical oxazolone on a shaved flank. Four days later, ear thickness was measured, compounds were applied topically in ethanol to one ear, ears were challenged with oxazolone, and swelling was measured 24 h post-challenge.
For the ovalbumin-induced airway inflammation model, mice were sensitized twice intraperitoneally with ovalbumilum. Ten days later, mice received intratracheal compound or vehicle for 3 consecutive days, with concurrent intranasal ovalbumin challenges. Airway hyperresponsiveness to 5-HT was assessed by whole-body plethysmography, and bronchoalveolar lavage was collected for inflammatory cell counts. |
| References |
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| Additional Infomation |
GW870086X has been investigated for the treatment of asthma. GW870086 is a novel steroidal glucocorticoid receptor ligand discovered through modification of the 17α site of a fluticasone template. It possesses unique "dissociative" pharmacological properties: it effectively inhibits pro-inflammatory genes and pathways (trans-inhibition), but exhibits extremely low activity against the activation of many classic glucocorticoid receptor (GR)-driven genes (trans-activation). It is considered a topical anti-inflammatory agent with a higher therapeutic index potential compared to classic glucocorticoids and is in clinical development for asthma at the time of publication.
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| Molecular Formula |
C31H39F2NO6
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|---|---|
| Molecular Weight |
559.641276597977
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| Exact Mass |
559.275
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| Elemental Analysis |
C, 66.53; H, 7.02; F, 6.79; N, 2.50; O, 17.15
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| CAS # |
827319-43-7
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| PubChem CID |
11376392
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| Appearance |
White to off-white solid powder
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| LogP |
4.582
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
|
| Heavy Atom Count |
40
|
| Complexity |
1280
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| Defined Atom Stereocenter Count |
9
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| SMILES |
O([C@@]1([C@H](C)C[C@H]2[C@@H]3C[C@H](F)C4=CC(C=C[C@]4(C)[C@]3([C@H](C[C@]12C)O)F)=O)C(=O)OCC#N)C(C1C(C)(C)C1(C)C)=O
|
| InChi Key |
WUBKGTSFJSEIEM-NSHBDUGJSA-N
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| InChi Code |
InChI=1S/C31H39F2NO6/c1-16-12-18-19-14-21(32)20-13-17(35)8-9-28(20,6)30(19,33)22(36)15-29(18,7)31(16,25(38)39-11-10-34)40-24(37)23-26(2,3)27(23,4)5/h8-9,13,16,18-19,21-23,36H,11-12,14-15H2,1-7H3/t16-,18+,19+,21+,22+,28+,29+,30+,31+/m1/s1
|
| Chemical Name |
Androsta-1,4-diene-17-carboxylic acid, 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-(((2,2,3,3-tetramethylcyclopropyl)carbonyl)oxy)-, cyanomethyl ester, (6alpha,11beta,16alpha,17alpha)-
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| Synonyms |
GW-870086; GW-870086X; 870086; GW870086; GW870086X; GW 870086; GW 870086X
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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) |
DMSO : ~100 mg/mL (~178.69 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.47 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 (4.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7869 mL | 8.9343 mL | 17.8686 mL | |
| 5 mM | 0.3574 mL | 1.7869 mL | 3.5737 mL | |
| 10 mM | 0.1787 mL | 0.8934 mL | 1.7869 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.
 GW870086 shows a range of activity on glucocorticoid-up-regulated genes compared with classical glucocorticoids in A549 cells.Br J Pharmacol.2013 Jul;169(6):1389-403. |
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 Effects of GW870086 on respiratory epithelial cell function.Br J Pharmacol.2013 Jul;169(6):1389-403. |
 GW870086 antagonizes the effect of dexamethasone on the MMTV reporter gene.
GW870086 retains transrepressive activity in A549 cells compared with classical glucocorticoids.Br J Pharmacol.2013 Jul;169(6):1389-403. |
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