| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
human Norepinephrine transporter 8.0 (pIC50) human Serotonin transporter 8.6 (pIC50) rat Norepinephrine transporter 7.9 (pIC50) rat Serotonin transporter 8.9 (pIC50)
NET (norepinephrine transporter) and SERT (serotonin transporter). Ampreloxetine inhibits the norepinephrine transporter (NET) with an EC50 of 11.7 ng/mL and the serotonin transporter (SERT) with an EC50 of 50.8 ng/mL in plasma. It shows no significant affinity for the dopamine transporter (DAT). |
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| ln Vitro |
Ampreloxetine binds NET and SERT with EC50 values of 11.7 ng/mL and 50.8 ng/mL in plasma, respectively. It has no activity at DAT. The compound is CNS-penetrant and acts as a long-acting inhibitor of norepinephrine reuptake, increasing synaptic norepinephrine concentrations to improve vasoconstriction and blood pressure regulation.
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| ln Vivo |
In rat models, ampreloxetine hydrochloride (0.3–60 mg/kg; oral; single dose) plasma concentrations are dose-independent[1].
In clinical studies, ampreloxetine increased standing blood pressure in patients with neurogenic orthostatic hypotension. The defining pharmacological characteristic is a prolonged plasma half-life of 30-40 hours, which supports once-daily dosing. The compound improves norepinephrine-mediated vasoconstriction, leading to durable improvement in orthostatic hypotension symptoms in MSA patients. Phase 3 trials have been conducted. |
| Enzyme Assay |
Cell-free NET binding assays: Human NET-expressing HEK293 cell membranes (10-20 ug) are incubated with [3H]-nisoxetine (1-5 nM) and increasing concentrations of ampreloxetine (0.01-1000 nM) in 50 mM Tris-HCl, pH 7.4, 150 mM NaCl, 5 mM KCl for 60 min at 25degC. Bound radioactivity is separated by GF/B filtration. Non-specific binding is determined with 10 uM desipramine. IC50 values are converted to Ki using the Cheng-Prusoff equation. SERT and DAT selectivity assays are performed similarly using [3H]-paroxetine and [3H]-WIN 35428, respectively.
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| Cell Assay |
Human NET-, SERT-, or DAT-expressing HEK293 cells are seeded in 96-well plates and pre-incubated with ampreloxetine (0.1-1000 nM) for 15 minutes. Cells are then incubated with 3H-labeled substrates ([3H]-NE for NET, [3H]-5-HT for SERT, [3H]-DA for DAT) for 5-10 minutes at 37degC. Uptake is terminated by aspiration and washing. Cells are lysed, and incorporated radioactivity is measured. EC50 values for inhibition of uptake are calculated. Reported EC50 values are 11.7 ng/mL (NET) and 50.8 ng/mL (SERT) in plasma.
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| Animal Protocol |
Animal/Disease Models: Rat[1]
Doses: 0.3, 1, 5, 10, 30, and 60mg/kg Route of Administration: PO; euthanized by decapitation at 0.5, 2, 4, 6, and 8 hr for 5mg/ kg dose level; 2 hr for 0.3, 1, 10, 30, and 60mg/kg dose levels Experimental Results: In the effect compartment PK/PD analysis for NET and SERT occupancy, the estimated EC50 for occupancy was 11.7ng/mL for NET and 50.8ng/mL for SERT in rat spinal cords, and the projected human plasma EC50 values were 5.5ng/mL for NET and 23.9ng/mL for SERT. In vivo efficacy studies are conducted in multiple system atrophy (MSA) patients and animal models of orthostatic hypotension. In preclinical models, ampreloxetine is administered orally to rats (0.3-10 mg/kg). Blood pressure is measured by tail-cuff plethysmography or telemetry. Norepinephrine levels in plasma and cerebrospinal fluid are measured by HPLC-ECD. For PK studies, ampreloxetine is administered orally to rats and dogs at doses of 1-10 mg/kg. Blood samples are collected at 0-72 hours post-dose for LC-MS/MS analysis. |
| ADME/Pharmacokinetics |
PK: prolonged plasma half-life of 30-40 hours, which supports once-daily oral dosing. Ampreloxetine is orally active, CNS-penetrant, and has high oral bioavailability. It exhibits dose-proportional pharmacokinetics. The compound is metabolized primarily by CYP enzymes. Steady state is achieved after approximately 5-7 days of once-daily dosing. Volume of distribution suggests extensive tissue distribution. Plasma protein binding is moderate to high.
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| Toxicity/Toxicokinetics |
No specific preclinical toxicity data are reported for ampreloxetine. In clinical trials, ampreloxetine has been generally well-tolerated. Common adverse events include headache, nausea, dizziness, and fatigue. As a norepinephrine reuptake inhibitor, potential safety concerns include hypertension, tachycardia, insomnia, and anxiety. Long-term safety is being evaluated in ongoing extension studies. No hepatotoxicity or cardiotoxicity signals have been reported.
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| References | |
| Additional Infomation |
Other information: Ampreloxetine is an investigational drug that has completed Phase 3 clinical trials for neurogenic orthostatic hypotension in patients with multiple system atrophy. The compound is not yet FDA-approved. It is characterized by a prolonged half-life (30-40 hours) enabling once-daily dosing. The CAS number is 1227056-87-2 (hydrochloride salt). It is available for research purposes only. The compound was originally developed by Theravance Biopharma.
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| Molecular Formula |
C18H19CLF3NO
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|---|---|
| Molecular Weight |
357.797774553299
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| Exact Mass |
357.11
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| Elemental Analysis |
C, 60.42; H, 5.35; Cl, 9.91; F, 15.93; N, 3.91; O, 4.47
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| CAS # |
1227056-87-2
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| Related CAS # |
Ampreloxetine;1227056-84-9; Ampreloxetine hydrochloride;1227056-87-2; 1227056-85-0 (TFA)
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| PubChem CID |
46189894
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
24
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| Complexity |
352
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C(C1C=CC=CC=1C1CCNCC1)OC1C(=CC(F)=CC=1F)F.Cl
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| InChi Key |
RVUPIJWDTBFULZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H18F3NO.ClH/c19-14-9-16(20)18(17(21)10-14)23-11-13-3-1-2-4-15(13)12-5-7-22-8-6-12;/h1-4,9-10,12,22H,5-8,11H2;1H
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| Chemical Name |
4-[2-[(2,4,6-trifluorophenoxy)methyl]phenyl]piperidine;hydrochloride
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| Synonyms |
Ampreloxetine hydrochloride; TD-9855 hydrochloride; TD9855 hydrochloride; TD 9855; 1227056-87-2; TD-9855 monohydrochloride; TD-9855 HCl; Ampreloxetine monohydrochloride;
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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: 100 mg/mL (279.49 mM)
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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 | 2.7949 mL | 13.9743 mL | 27.9486 mL | |
| 5 mM | 0.5590 mL | 2.7949 mL | 5.5897 mL | |
| 10 mM | 0.2795 mL | 1.3974 mL | 2.7949 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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