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Purity: ≥98%
Vilanterol trifenatate (formerly GW-642444; Anoro Ellipta; Breo Ellipta), the trifenatate salt of vilanterol, is an ultra-long-acting β2-adrenoceptor/ beta-2 (β2-AR) agonist approved in May 2013 for use in combination with fluticasone furoate (Breo Ellipta) and also in combination with Umeclidinium bromide (Anoro Ellipta) for the treatment of chronic obstructive pulmonary disease (COPD).The pEC50 values for β2-AR, β1-AR, and β3-AR are 10.37±0.05, 6.98±0.03, and 7.36±0.03, in that order.
| Targets |
β2-adrenoceptor
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|---|---|
| ln Vitro |
Vilanterol exhibits a subnanomolar affinity for the β2-AR that is greater than that of olodaterol, formoterol, and indacaterol, but similar to salmeterol's. Vilanterol shows comparable selectivity to salmeterol for β2-over β1-AR and β3-AR in cAMP functional activity studies, but a markedly better selectivity profile than formoterol and indacaterol. Additionally, vilanterol exhibits an intrinsic efficacy that is notably higher than salmeterol but comparable to indacaterol. Vilanterol exhibits a longer duration of action than formoterol and a persistence of action similar to indacaterol in tissue-based studies measuring persistence and reassertion and cellular cAMP production. Furthermore, vilanterol exhibits reassertion activity in tissue and cell systems that is longer than formoterol but comparable to salmeterol and indacaterol. Vilanterol has been demonstrated to exhibit a significant degree of bronchodilation 22 hours after treatment, with a faster onset and longer duration of action in human airways than salmeterol[1].
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| ln Vivo |
Compound 13f (vilanterol) had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration[2].
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| Enzyme Assay |
For [3H]Vilanterol, binding kinetics studies involving saturation, association, and dissociation are carried out to calculate the equilibrium dissociation constant (KD), total number of receptors (Bmax), association rate (kon), and dissociation rate (koff). Membranes are filtered after being incubated with increasing concentrations of [3H]Vilanterol (0.01-1.3 nM) for 5 hours to achieve saturation binding (in a volume of 1.4 mL to prevent ligand depletion). Membranes are incubated with varying concentrations of [3H]Vilanterol (0.1-1.9 nM) for up to 1 hour prior to filtration in order to facilitate association binding. Membranes are preincubated with a fixed concentration of [3H]Vilanterol (1.1 nM) for 1 hour in order to facilitate dissociation binding. Dissociation is then triggered by dilution in binding buffer (10 μM cold Vilanterol), and incubation is continued for variable periods up to 8 hours prior to filtration. As with [3H]Vilanterol, saturation binding is also accomplished for [3H]CGP12177 (with concentrations rising to approximately 0.01-2.8 nM). Competition binding displacement studies, in which membranes are incubated with a fixed concentration of [3H]Vilanterol (0.2 nM) and increasing concentrations of unlabeled agonist/antagonist for 5 h before filtration, are carried out to ascertain the affinity of β2-AR agonists and antagonists. To guarantee that binding curves are monophasic, 100 µM Gpp(NH)p is present during the completion of all competition binding displacement studies[1].
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| Cell Assay |
DiscoveRx cAMP (Whole Cell) Adrenergic β1, β2 and β3 Agonist Assay [5]
The HitHunter DiscoveRx cAMP assay uses a split enzyme complementation readout to capture the content of cAMP either in whole cells or generated from cell membranes. The split enzyme used in the assay is β-galactosidase which is measured using a luminescence readout. Briefly, CHO cells expressing either human β1, β2 or β3 were thawed at room temperature, diluted in PBS and centrifuged. Cells were then resuspended at (2 million cells/mL) in phenol red free DMEM containing 10 µM IBMX. 20000 cells were added to a 384-well plate containing the test compound and incubated for 30-45 min. The cAMP content was measured as per the HitHunter DiscoveRx kit instructions. Basically, the cells were lysed and an antibody to cAMP added along with the two fragments of β-gal one linked to cAMP (enzyme donor) and one to 19 enzyme acceptor to form active enzyme. The substrate was hydrolyzed by the active enzyme for EFC detection (luminescence) of β-gal activity. The final assay cocktail was incubated at room temperature to equilibrate for 3 hours before reading on a Viewlux. All compounds were dissolved in DMSO at a concentration of 10 mM and the DMSO concentration was constant across the plate for all assays. All data was normalized to the mean of 16 high and 16 low control wells on each plate. Four parameter logistic fits were then performed on the normalized data to determine the pEC50 and maximum asymptote values. The values quoted are arithmetic mean ± SEM. The intrinsic activity (IA) was determined by dividing the maximum asymptote ratio obtained for the test compound by the maximum asymptote ratio obtained for isoprenaline. The values quoted for the intrinsic activity are the geometric mean and lower and upper 95% confidence limits. The selectivity ratio was determined by subtracting the pEC50 for either β1 or β3 from that of the β2 pEC50 generated from the potency.
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| Animal Protocol |
Pharmacokinetic studies in rats.[5]
Male Han Wistar rats (bodyweight about 250 g) were fasted for 18 h prior to dose administration. 13f (Vilanterol) acetate salt was formulated as a solution in DMSO-PEG 200- distilled water (10:30:60, v/v/v) for oral dosing, and DMSO-saline (10:90, v/v) for intravenous dosing. Rats were dosed orally by gavage tube or intravenously via a tail vein at nominal dose levels of 2 mg 13f base/kg or 0.25 mg 13f base/kg respectively. Blood samples were taken by cardiac puncture at 0.03 (intravenous only), 0.08, 0.25, 0.5, 0.75, 1, 2, 3 (oral only), 4, 6, and 8 h post dose (n=2 animals/time-point). Plasma was prepared from blood by centrifugation, and analyzed for 13f content by LCMS/MS. Non-compartmental methods were used to calculate pharmacokinetic parameters from plasma concentration vs time profiles.
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| References |
[2]. Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach. J Med Chem . 2010 Jun 10;53(11):4522-30. doi: 10.1021/jm100326d.
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| Additional Infomation |
Vilanterol trifenate is a triphenylacetate salt obtained by combining vilanterol with one equivalent of triphenylacetic acid. Used in combination with fluticasone furoate for treatment of bronchospasm associated with chronic obstructive pulmonary disease. It has a role as a beta-adrenergic agonist and a bronchodilator agent. It contains a vilanterol(1+).
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| Molecular Formula |
C44H49CL2NO
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|---|---|
| Molecular Weight |
774.76836
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| Exact Mass |
773.288
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| Elemental Analysis |
C, 68.21; H, 6.38; Cl, 9.15; N, 1.81; O, 14.45
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| CAS # |
503070-58-4
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| Related CAS # |
Vilanterol; 503068-34-6; Vilanterol-d4 trifenatate; 2021249-10-3; 503070-58-4 (trifenatate)
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| PubChem CID |
44482554
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| Appearance |
White to off-white solid powder
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| Melting Point |
131.9-134.2℃
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| LogP |
9.104
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
20
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| Heavy Atom Count |
54
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| Complexity |
778
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| Defined Atom Stereocenter Count |
1
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| SMILES |
OC1=CC=C([C@@H](O)CNCCCCCCOCCOCC2=C(Cl)C=CC=C2Cl)C=C1CO.O=C(O)C(C3=CC=CC=C3)(C4=CC=CC=C4)C5=CC=CC=C5
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| InChi Key |
KLOLZALDXGTNQE-JIDHJSLPSA-N
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| InChi Code |
InChI=1S/C24H33Cl2NO5.C20H16O2/c25-21-6-5-7-22(26)20(21)17-32-13-12-31-11-4-2-1-3-10-27-15-24(30)18-8-9-23(29)19(14-18)16-28;21-19(22)20(16-10-4-1-5-11-16,17-12-6-2-7-13-17)18-14-8-3-9-15-18/h5-9,14,24,27-30H,1-4,10-13,15-17H2;1-15H,(H,21,22)/t24-;/m0./s1
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| Chemical Name |
4-[(1R)-2-[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol;2,2,2-triphenylacetic acid
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| Synonyms |
GW-642444; GW 642444-X; GW 642444 X; GW642444; GW-642444; GW 642444X; Anoro Ellipta; Breo Ellipta
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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. |
| 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: 50~100 mg/mL (64.5~129.1 mM)
Ethanol: ~14 mg/mL |
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2 mg/mL (2.58 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 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 mg/mL (2.58 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 20.0 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 mg/mL (2.58 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.2907 mL | 6.4535 mL | 12.9071 mL | |
| 5 mM | 0.2581 mL | 1.2907 mL | 2.5814 mL | |
| 10 mM | 0.1291 mL | 0.6454 mL | 1.2907 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01498679 | Completed | Drug: GW685698/GW642444 (fluticasone furoate/vilanterol trifenatate) |
Asthma | GlaxoSmithKline | January 2012 | Phase 3 |
| NCT03184987 | Completed | Drug: FF/UMEC/VI 100/62.5/25 mcg Drug: FF/UMEC/VI 200/62.5/25 mcg Drug: Salbutamol |
Asthma | GlaxoSmithKline | June 22, 2017 | Phase 3 |
| NCT05062304 | Completed | Drug: Vicriviroc maleate Drug: Placebo |
HIV Infections | Merck Sharp & Dohme LLC | July 2007 | N/A |
| NCT03739294 | Completed | Drug: Fluticasone Furoate/ Vilanterol Trifenatate |
Pharmacokinetics | Bispebjerg Hospital | February 8, 2019 | Phase 2 |
| NCT01498653 | Completed | Drug: GW685698/GW642444 Drug: CCI18781 |
Asthma | GlaxoSmithKline | January 2012 | Phase 3 |
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