| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
|
||
| 5mg | |||
| Other Sizes |
| Targets |
OX2R (orexin type 2 receptor). Danavorexton induces a physiological pattern of OX2R activation and shows >5000-fold selectivity against OX1R in calcium mobilization assays.
|
|---|---|
| ln Vitro |
Danavorexton shows potent agonistic activity for recombinant human OX2R with an EC50 value of 5.5 nM and >5000-fold selectivity against OX1R in calcium mobilization assays. It shows rapid association/dissociation kinetics to OX2R, enabling precise control of receptor activation.
|
| ln Vivo |
In common marmosets and cynomolgus monkeys, danavorexton (1, 10 mg/kg or 1, 3 mg/kg, subcutaneously) increases arousal in a dose-dependent manner[2].
Danavorexton provides symptomatic improvement in narcolepsy mouse models. Following subcutaneous administration (10 mg/kg), TAK-925 significantly increases wakefulness time and reduces cataplexy-like episodes in orexin/ataxin-3 transgenic mice. The compound induces a physiological pattern of OX2R activation in vitro to wake up sleepy mice and improve sleepiness symptoms. |
| Enzyme Assay |
Cell-free functional assays for OX2R agonism are performed using membrane preparations from CHO-K1 cells stably expressing human OX2R. Increasing concentrations of danavorexton are incubated with 35S-GTPgammaS (0.1 nM) and membrane protein (10-20 microg/well) in assay buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl2) for 60 min at 25degC. Bound radioactivity is separated by GF/B filter filtration and quantified by liquid scintillation counting. EC50 is derived from nonlinear regression.
|
| Cell Assay |
For calcium mobilization assays, CHO-K1 cells expressing human OX2R or OX1R are seeded in 384-well plates and loaded with a calcium-sensitive fluorescent dye. Danavorexton is added at increasing concentrations (0.1 nM to 10 uM). Fluorescence is measured using a FLIPR or FDSS plate reader. EC50 for OX2R is determined from dose-response curves. For selectivity assessment, the same assay is performed using OX1R-expressing cells.
|
| Animal Protocol |
Animal/Disease Models: Common marmosets and cynomolgus monkeys models[2]
Doses: 1, 10 mg/kg (1, 3 mg/kg) Route of Administration: sc Experimental Results: diminished SWS I (Sleeping With Sirens I), SWS II (Sleeping With Sirens II ) and REM (Rapid Eye Movement) sleep time. In vivo pharmacology studies are conducted in orexin/ataxin-3 transgenic narcolepsy mice. Danavorexton is administered subcutaneously (3-30 mg/kg) or intraperitoneally at 10 mg/kg. Sleep/wake states are monitored by EEG/EMG telemetry for 4-6 hours post-dose. Parameters assessed include wakefulness time, NREM sleep, REM sleep, and cataplexy episode frequency. Brain and plasma samples are collected for PK/PD correlation. For PK studies, mice receive danavorexton at 10 mg/kg s.c., with blood and brain collected at 0.25, 0.5, 1, 2, 4, 8, 12, 24 h post-dose and analyzed by LC-MS/MS. |
| ADME/Pharmacokinetics |
Danavorexton shows brain-penetrant properties with a free brain/plasma ratio allowing central OX2R engagement. Following subcutaneous administration in mice at 10 mg/kg, TAK-925 reaches peak brain concentrations within 0.5-1 hour. The compound exhibits moderate clearance and a half-life suitable for once- or twice-daily dosing in preclinical species. Unbound fraction is determined by rapid equilibrium dialysis.
|
| Toxicity/Toxicokinetics |
Preclinical toxicology studies in rodents and non-human primates demonstrate that danavorexton is generally well-tolerated at therapeutic doses. No significant hepatotoxicity or nephrotoxicity has been reported in animal studies to date. Common adverse events in Phase 1 clinical trials included mild gastrointestinal symptoms and headache. The overall safety profile is more favorable than TAK-994.
|
| References |
|
| Additional Infomation |
Other information: Danavorexton (TAK-925) is currently in clinical development as an orexin replacement therapy for narcolepsy type 1. Unlike TAK-994, which was discontinued due to safety concerns, TAK-925 continues development with ongoing Phase 2 trials. It is designed to restore wakefulness by selectively activating OX2R without the hepatic and renal toxicity seen with TAK-994. The compound represents a promising therapeutic approach for patients with narcolepsy type 1.
|
| Molecular Formula |
C21H32N2O5S
|
|---|---|
| Molecular Weight |
424.55
|
| Exact Mass |
424.203
|
| CAS # |
2114324-48-8
|
| PubChem CID |
130310079
|
| Appearance |
White to off-white solid powder
|
| LogP |
2.7
|
| Hydrogen Bond Donor Count |
1
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
7
|
| Heavy Atom Count |
29
|
| Complexity |
622
|
| Defined Atom Stereocenter Count |
2
|
| SMILES |
C1=CC=CC([C@@H]2CC[C@H](OC[C@H]3[C@@H](NS(=O)(=O)C)CCCN3C(OC)=O)CC2)=C1
|
| InChi Key |
UXZAJSZFFARTEI-GUMHCPJTSA-N
|
| InChi Code |
InChI=1S/C21H32N2O5S/c1-27-21(24)23-14-6-9-19(22-29(2,25)26)20(23)15-28-18-12-10-17(11-13-18)16-7-4-3-5-8-16/h3-5,7-8,17-20,22H,6,9-15H2,1-2H3/t17?,18?,19-,20-/m0/s1
|
| Chemical Name |
methyl (2R,3S)-3-(methanesulfonamido)-2-[(4-phenylcyclohexyl)oxymethyl]piperidine-1-carboxylate
|
| HS Tariff Code |
2934.99.9001
|
| 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)
|
| 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
|
|---|---|
| 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 | 2.3554 mL | 11.7772 mL | 23.5544 mL | |
| 5 mM | 0.4711 mL | 2.3554 mL | 4.7109 mL | |
| 10 mM | 0.2355 mL | 1.1777 mL | 2.3554 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.
Link: https://clinicaltrials.gov/ct2/show/NCT05814016
Conditions:Sleep ApneaLink: https://clinicaltrials.gov/ct2/show/NCT04091438
Conditions:Idiopathic HypersomniaLink: https://clinicaltrials.gov/ct2/show/NCT05180890
Conditions:Sleep Apnea
Title:A Study of Danavorexton in Anesthetized Adults
Status:Completed
updateDate:2022-05-10
Ctid:NCT05025397
Link: https://clinicaltrials.gov/ct2/show/NCT05025397
Conditions:Healthy VolunteersLink: https://clinicaltrials.gov/ct2/show/NCT03332784
Conditions:Healthy Participants and Patients With NarcolepsyLink: https://clinicaltrials.gov/ct2/show/NCT03522506
Conditions:Healthy VolunteersLink: https://clinicaltrials.gov/ct2/show/NCT03748979
Conditions:Healthy Participants|NarcolepsyLink: https://clinicaltrials.gov/ct2/show/NCT04091425
Conditions:Obstructive Sleep ApneaProducts are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
