| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| 50mg |
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| Other Sizes |
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| Targets |
5-HT3 Receptor
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| ln Vitro |
Cisplatin cytotoxicity was not impacted by the addition of (R)-Azasetron besylate (SENS-401)
(up to 10 μM) in any of the cell types evaluated. In vitro data support the otoprotective potential and tolerability of SENS-401 without impacting chemotherapeutic potential[2].
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| ln Vivo |
All (R)-Azasetron besylate (SENS-401)
doses improved ABR threshold shift and recovery, reaching statistical significance (p < 0.05) for ABR threshold recoveries after 28-days treatment. DPOAE amplitude loss and recovery improved markedly for 13.2 mg/kg BID SENS-401, reaching significance after 14 days (p < 0.05). Significant improvements in ABR threshold shifts/recovery and DPOAE amplitude loss occurred with up to 96-hours delay in initiating SENS-401 (p < 0.05), and in DPOAE amplitude recovery with up to 72-hours delay (p < 0.05). Significantly more surviving OHCs were present after SENS-401 treatment compared with placebo after 24 to 96-hours delay posttrauma, with up to 5.3-fold more cells in the basal cochlea turn.
Conclusions: In vivo data support the otoprotective potential of twice daily oral SENS-401. Improvements in hearing loss recovery make SENS-401 a promising clinical candidate for acoustic trauma-induced hearing loss, including when treatment is not initiated immediately.[1]
In vivo, all SENS-401 doses significantly improved auditory brainstem response threshold shift (up to 30 dB) and distortion product otoacoustic emission amplitude loss (up to 19 dB) over placebo. Body weight and survival were not significantly different between rats receiving placebo and those receiving 26.4 mg/kg SENS-401. Significantly more surviving outer hair cells were present after SENS-401 treatment compared with placebo (p < 0.001), with up to 11-fold more in the basal turn of the cochlea[2]. |
| Cell Assay |
MTS Cytotoxicity Assay[2]
Cells were seeded at the optimal seeding density in 96-well Nunc plates and incubated for 24 hours. Cisplatin cytotoxicity was evaluated after 96 hours treatment with a range of concentrations (0.12, 0.37, 1.1, 3.3, 10 μM), alone (DMSO control) or with different (R)-Azasetron besylate (SENS-401) concentrations (0.12, 0.37, 1.1, 3.3, and 10 μM in DMSO). After exposure, MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulfophenyl)-2H-tetrazolium; 20 mL at 2 mg/mL) and the electron coupling reagent phenazine methosulfate (1 mL at 0.92 mg/mL) in Dulbecco's PBS were added. Absorbance was measured at 490 nm using a VICTOR3 1420 multilabel counter. Two independent experiments were performed in triplicate. IC50 values (drug concentration to obtain 50% inhibition of cell proliferation) were calculated using XLFit5 software. |
| Animal Protocol |
The dose-response relationship of SENS-401 (6.6 mg/kg BID, 13.2 mg/kg BID, 26.4 mg/kg QD) and treatment time-window (13.2 mg/kg BID starting 24, 72, and 96 h posttrauma) versus placebo for 28 days were evaluated in a male rat model of severe acoustic trauma-induced hearing loss (120 dB SPL, 2 h) using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) measures followed by cochlear outer hair cell (OHC) counting with myosin-VIIa immunolabeling.[1]
For audiometry experiments, female 5-week-old Wistar rats ∼150 g were housed for 2 weeks before experimentation in a temperature-controlled environment with a 12-hours light/dark cycle and free access to water and food. They were randomly divided into groups of 8 to 13 animals. All rats received cisplatin (8 mg/kg in saline) on day 1 as a 30-minute intravenous injection under isoflurane anesthesia. (R)-Azasetron besylate (SENS-401) (6.6, 13.2, 26.4 mg/kg/d, 0.9% NaCl) or placebo (0.9% NaCl) were given orally for 14 days using a gavage needle dipped in sucrose (14), initiated 15 minutes before cisplatin. Animals were weighed from Day 1 to 14, before the daily treatment. Two successive series of ABR and DPOAE experiments were performed, the first comparing placebo with 26.4 mg/kg/d SENS-401 and the second comparing placebo with 6.6 and 13.2 mg/kg/d SENS-401. Evaluations were performed at baseline (pre-exposure) 2 days before treatment initiation, and after 14 days of SENS-401/placebo. Animals were deeply anesthetized throughout the audiometry experiments using 80 mg/kg ketamine, 8 mg/kg xylazine, and 1 mg/kg acepromazine inside a sound-proof chamber. After audiometry tests on day 14, four to five animals per treatment group were sacrificed for immunolabeling.[2] For pharmacokinetics experiments, male 7-week-old Wistar rats aged ∼325 g were maintained as described above. They were randomly divided into groups of 24 animals (four rats sacrificed per time point), each receiving a single dose of oral SENS-401 (6.6, 13.2, 26.4 mg/kg/d, 0.9% NaCl) using a gavage needle.[2] |
| References |
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| Additional Infomation |
Arazasetron Besylate is the besylate salt form of the R-enantiomer of azasetron, a benzamide derivative and selective serotonin (5-hydroxytryptamine; 5-HT) receptor and calcineurin antagonist, with potential antinauseant and antiemetic, and otoprotective activities. Upon administration, arazasetron selectively binds to and inhibits 5-HT subtype 3 receptors (5-HT3R) located peripherally on vagus nerve terminals and centrally in the chemoreceptor trigger zone (CTZ) of the area postrema, which may result in suppression of nausea and vomiting. R-azasetron also targets and inhibits the activation of calcineurin, thereby preventing inner ear lesions, nerve degeneration, induction of apoptosis and sensory hair loss. This may prevent hearing loss. Calcineurin activation plays a key role in structural degeneration, swelling, synaptic uncoupling and the induction of apoptosis in the inner ear leading to hair cell loss and hearing loss.
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| Molecular Formula |
C23H26CLN3O6S
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|---|---|
| Molecular Weight |
507.987043857574
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| Exact Mass |
507.123
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| Elemental Analysis |
C, 54.38; H, 5.16; Cl, 6.98; N, 8.27; O, 18.90; S, 6.31
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| CAS # |
2025360-91-0
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| Related CAS # |
123040-69-7; 2025360-91-0 (besylate); 123040-16-4 (HCl)
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| PubChem CID |
131801108
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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 |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
34
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| Complexity |
707
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CN1C(=O)COC2=C(C=C(C=C21)Cl)C(=O)N[C@H]3CN4CCC3CC4.C1=CC=C(C=C1)S(=O)(=O)O
|
| InChi Key |
GFVBDLIBPSGFDL-ZOWNYOTGSA-N
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| InChi Code |
InChI=1S/C17H20ClN3O3.C6H6O3S/c1-20-14-7-11(18)6-12(16(14)24-9-15(20)22)17(23)19-13-8-21-4-2-10(13)3-5-21;7-10(8,9)6-4-2-1-3-5-6/h6-7,10,13H,2-5,8-9H2,1H3,(H,19,23);1-5H,(H,7,8,9)/t13-;/m0./s1
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| Chemical Name |
N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide;benzenesulfonic acid
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| Synonyms |
(R)-Azasetron besylate; R-Azasetron besylate; 2025360-91-0; UXP39EQ477; (R)-Azasetron (besylate); ARAZASETRON BESYLATE; UNII-UXP39EQ477; ARAZASETRON;
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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) |
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 | 1.9685 mL | 9.8427 mL | 19.6854 mL | |
| 5 mM | 0.3937 mL | 1.9685 mL | 3.9371 mL | |
| 10 mM | 0.1969 mL | 0.9843 mL | 1.9685 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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