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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| Targets |
Soticlestat targets cholesterol 24-hydroxylase (CH24H/CYP46A1), an enzyme that regulates cholesterol metabolism in the brain. By inhibiting CH24H, the compound lowers brain 24S-hydroxycholesterol levels. This modulation of cholesterol metabolism is thought to reduce neural hyperexcitation and has therapeutic potential for severe epilepsy syndromes through effects on glutamate signaling and synaptic plasticity.
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| ln Vitro |
Human cholesterol 24-gradient enzyme (CH24H) catalytic activity is inhibited by soticlestat in a concentration suspension manner, with an IC50 of 4.5 nM[1].
In vitro, Soticlestat is a potent and selective inhibitor of cholesterol 24-hydroxylase (CH24H) with an IC50 of 0.0074 µM. It shows selectivity for CH24H over other CYP isoforms, including CYP2C8, -2C9, -2D6, -3A4, -1A2, and 2C19 (IC50s = 62, 19, >100, 66, >100, and 14 µM, respectively), confirming its specificity. |
| ln Vivo |
Treatment with soticlestat decreased brain 24S-pivot dormancy dose-dependently and at dosages that decreased brain 24S-pivot by about 50%, greatly decreased premature death in the APP/PS1-Tg pivot. Presetilin 1 (APP/PS1-Tg) and amyloid precursor protein (APP/PS1)-producing hippocampal mouse model that Soticlestat can potentially trigger (7 weeks old) [1]
In vivo, Soticlestat lowers brain 24S-hydroxycholesterol in a dose-dependent manner. It substantially reduces premature deaths of APP/PS1-Tg mice at a dose that lowers brain 24S-hydroxycholesterol by approximately 50%. It has shown potential in models of epilepsy by reducing seizure frequency and severity, supporting its clinical development. |
| Enzyme Assay |
In vitro enzyme assays for Soticlestat typically measure the inhibition of cholesterol 24-hydroxylase (CH24H) activity. The enzyme is incubated with its substrate (cholesterol) in the presence of varying concentrations of the compound. The production of 24S-hydroxycholesterol is measured (e.g., by LC-MS/MS), and the IC50 is determined from dose-response curves.
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| Cell Assay |
In vitro cellular assays for Soticlestat are not typically performed, as its primary target is an enzyme involved in cholesterol metabolism in the brain. Its effects can be studied in cell lines that express CH24H (e.g., neuronal cell lines) by measuring the levels of 24S-hydroxycholesterol in the culture medium after compound treatment.
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| Animal Protocol |
Animal/Disease Models: Amyloid precursor protein and presenilin 1 (APP/PS1-Tg) mice (7weeks old)[1]
Doses: 10 mg/kg Route of Administration: Oral administration; one time/day; for 1 days, 3 days and 7 days Experimental Results:Lowered brain 24S-hydroxycholesterol in a dose-dependent manner and substantially diminished premature deaths of APP/PS1-Tg mice at a dose lowering brain 24S-hydroxycholesterol by approximately 50%.. In vivo animal models for Soticlestat include APP/PS1-Tg mice to study its effects on brain 24S-hydroxycholesterol levels and survival. Models of epilepsy, such as the Dravet syndrome mouse model or the maximal electroshock seizure test, are also used to evaluate its anti-seizure efficacy. The compound is typically administered orally. |
| ADME/Pharmacokinetics |
Soticlestat has a molecular formula of C23H23N3O2 and a molecular weight of 373.45 g/mol. It is a first-in-class, orally active CH24H inhibitor. The compound is typically stored as a powder at -20°C for long-term stability. It is soluble in DMSO and should be protected from light and moisture.
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| Toxicity/Toxicokinetics |
Soticlestat is a CH24H inhibitor with a well-characterized mechanism of action. As with any experimental compound, potential toxicity should be evaluated in preclinical studies. In clinical trials, it has been generally well-tolerated, but common adverse effects may include somnolence, headache, and gastrointestinal disturbances. It is for research use only.
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| References | |
| Additional Infomation |
Drug Indication
Treatment of Dravet syndrome, treatment of Lennox-Gastaut syndrome; treatment of 15q chromosome duplication syndrome, treatment of cyclin-dependent kinase-like 5 deficiency. Soticlestat, also known as TAK-935 or OV935, is a first-in-class, potent, selective, and orally active inhibitor of cholesterol 24-hydroxylase (CH24H). It is being developed for epilepsy syndromes. The compound is for research use only and is not approved for human therapeutic use. |
| Molecular Formula |
C23H23N3O2
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|---|---|
| Molecular Weight |
373.46
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| Exact Mass |
373.179
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| CAS # |
1429505-03-2
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| PubChem CID |
73437845
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
597.4±50.0 °C at 760 mmHg
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| Flash Point |
315.1±30.1 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.637
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| LogP |
1.23
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
28
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| Complexity |
506
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
XKUZMIUSBMCVPP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H23N3O2/c27-22(20-7-4-12-25-21(20)19-8-13-24-14-9-19)26-15-10-23(28,11-16-26)17-18-5-2-1-3-6-18/h1-9,12-14,28H,10-11,15-17H2
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| Chemical Name |
(4-benzyl-4-hydroxypiperidin-1-yl)-(2-pyridin-4-ylpyridin-3-yl)methanone
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| Synonyms |
Soticlestat
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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 |
| 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 (~267.77 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.69 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (6.69 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (6.69 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6777 mL | 13.3883 mL | 26.7766 mL | |
| 5 mM | 0.5355 mL | 2.6777 mL | 5.3553 mL | |
| 10 mM | 0.2678 mL | 1.3388 mL | 2.6777 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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