| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
| Targets |
EC50: 19 nM (OX2R)[1]
OX2R (orexin type 2 receptor). TAK-994 is a selective OX2R agonist designed to replace the missing orexin neuropeptides in NT1 patients. |
|---|---|
| ln Vitro |
Activation of OX2R by TAK-994 promotes wakefulness and regulates sleep-wake cycles. It has shown strong efficacy in early clinical trials, significantly improving wakefulness and reducing sleep attacks. In CHO cells expressing OX2R, TAK-994 potently increases intracellular calcium.
|
| ln Vivo |
In Phase 2 clinical trials in NT1 patients, TAK-994 (30-180 mg twice daily) significantly improved MWT sleep latency by 23.9-32.6 min (vs -2.5 for placebo) and reduced ESS scores by 12.2-15.1 (vs -2.1 for placebo). Cataplexy rates were reduced to 0.27-1.14 episodes/week vs 5.83 for placebo. Both Phase 2 and extension trials were terminated early due to hepatic and renal adverse events.
|
| Enzyme Assay |
Cell-free functional assays for OX2R agonism are performed using membranes from CHO-K1 cells stably expressing human OX2R. Increasing concentrations of TAK-994 are incubated with 35S-GTPgammaS and membrane preparations in assay buffer (20 mM HEPES, 100 mM NaCl, 10 mM MgCl2, pH 7.4) for 60 min at 25degC. Bound radioactivity is separated by filtration, and EC50 values are determined by nonlinear regression.
|
| Cell Assay |
CHO-K1 cells expressing human OX2R are loaded with a calcium-sensitive fluorescent dye (Fluo-4 AM). TAK-994 at varying concentrations is added to the cells, and intracellular calcium flux is measured in real-time using a FLIPR or fluorescence microplate reader. EC50 for OX2R activation is determined by calculating the concentration required to produce 50% of the maximal calcium signal response.
|
| Animal Protocol |
In vivo animal protocols for TAK-994 used orexin/ataxin-3 transgenic narcolepsy mouse models. TAK-994 was administered via oral gavage or subcutaneous injection at doses ranging from 3-30 mg/kg. Wakefulness was measured by EEG/EMG recordings. For PK studies, blood and brain samples were collected at various time points post-dose (0.25, 0.5, 1, 2, 4, 8, 24 h) and analyzed by LC-MS/MS.
|
| ADME/Pharmacokinetics |
PK parameters: TAK-994 crosses the blood-brain barrier with oral bioavailability. Preclinical PK studies indicate brain penetration with a brain-to-plasma ratio suitable for CNS activity. Clinical PK was dose-proportional with Tmax around 1-2 hours post oral administration. The compound is metabolized primarily by CYP enzymes in the liver.
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| Toxicity/Toxicokinetics |
Development was discontinued in Phase 2 due to safety concerns. Renal and urinary treatment-emergent adverse events were reported in 24 subjects receiving TAK-994 (only 1 in placebo group). Clinically important elevations in liver-enzyme levels occurred in 5 patients, with drug-induced liver injury meeting Hy‘s law criteria in 2 patients.
|
| References | |
| Additional Infomation |
Other information: Development of TAK-994 was terminated in October 2021 following reports of hepatic and renal toxicity. Despite robust efficacy in narcolepsy type 1, the safety profile prevented further clinical development. (2R,3R)-Firazorexton is the isomeric free base form. TArousal, a related OX2R agonist, continues development. All products listed are for research use only and not for clinical use.
|
| Molecular Formula |
C44H56F6N4O11S2
|
|---|---|
| Molecular Weight |
995.056071281433
|
| Exact Mass |
994.329
|
| CAS # |
2861934-86-1
|
| Related CAS # |
Firazorexton;2274802-95-6;(2R,3R)-Firazorexton;2692692-00-3
|
| PubChem CID |
169490720
|
| Appearance |
White to off-white solid powder
|
| Hydrogen Bond Donor Count |
7
|
| Hydrogen Bond Acceptor Count |
19
|
| Rotatable Bond Count |
12
|
| Heavy Atom Count |
67
|
| Complexity |
766
|
| Defined Atom Stereocenter Count |
4
|
| SMILES |
CC(C)(C(=O)N1CC[C@@H]([C@@H]1CC2=C(C(=CC=C2)C3=CC(=CC(=C3)F)F)F)NS(=O)(=O)C)O.CC(C)(C(=O)N1CC[C@@H]([C@@H]1CC2=C(C(=CC=C2)C3=CC(=CC(=C3)F)F)F)NS(=O)(=O)C)O.O.O.O
|
| InChi Key |
XNRBNIWRMZALLM-JRMNKBLGSA-N
|
| InChi Code |
InChI=1S/2C22H25F3N2O4S.3H2O/c2*1-22(2,29)21(28)27-8-7-18(26-32(3,30)31)19(27)11-13-5-4-6-17(20(13)25)14-9-15(23)12-16(24)10-14;;;/h2*4-6,9-10,12,18-19,26,29H,7-8,11H2,1-3H3;3*1H2/t2*18-,19-;;;/m00.../s1
|
| Chemical Name |
N-[(2S,3S)-2-[[3-(3,5-difluorophenyl)-2-fluorophenyl]methyl]-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]methanesulfonamide;trihydrate
|
| 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 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)
|
| 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 | 1.0050 mL | 5.0248 mL | 10.0496 mL | |
| 5 mM | 0.2010 mL | 1.0050 mL | 2.0099 mL | |
| 10 mM | 0.1005 mL | 0.5025 mL | 1.0050 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.
Products are for research use only; We do not sell to patients
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