| Size | Price | Stock | Qty |
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| 1mg |
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| Other Sizes |
| Targets |
The primary target of (9R)-RO7185876 is gamma-secretase, a multi-subunit intramembrane protease complex. This complex is responsible for the final cleavage of APP to generate Abeta peptides of varying lengths (Abeta37, Abeta38, Abeta40, Abeta42). By inhibiting gamma-secretase, the compound reduces the production of Abeta42, the most aggregation-prone and neurotoxic form of Abeta.
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| ln Vitro |
The key in vitro activity of (9R)-RO7185876 is its ability to inhibit the secretion of Abeta42 from cells in culture. This has been demonstrated in cell-based assays using relevant neuronal or cell lines expressing APP. By blocking the proteolytic activity of gamma-secretase, the compound prevents the production of this pathogenic peptide. Its selectivity against other gamma-secretase substrates (e.g., Notch) is not described in the summary.
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| ln Vivo |
The in vivo activity of (9R)-RO7185876 has not been detailed in the summarized literature. However, the compound is described for use in research on Alzheimer's disease and related disorders, such as cerebral amyloid angiopathy and multi-infarct dementia. This suggests its utility in animal models where it would be administered to reduce Abeta42 levels in the brain and potentially ameliorate cognitive deficits.
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| Enzyme Assay |
A typical gamma-secretase activity assay: Cell membrane preparations containing gamma-secretase are incubated with a fluorogenic APP-based substrate (e.g., the C100Flag substrate). The reaction buffer contains 25 mM HEPES (pH 7.0), 0.1% CHAPSO, and 1 mM EDTA. The test compound (0.001-100 uM) is pre-incubated with the enzyme for 30 minutes. The reaction is started by adding the substrate. After 2 hours at 37degC, the reaction is stopped. The fluorescence of the cleaved product is measured (Ex 355 nm/Em 460 nm). The IC50 is calculated from the inhibition curve.
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| Cell Assay |
A standard cellular assay to measure Abeta42 production: HEK293 cells stably expressing the APP695 gene (or Swedish mutant APP) are seeded in 96-well plates. The following day, the cells are treated with various concentrations (0.1 pM to 1 uM) of (9R)-RO7185876 for 16-24 hours. The levels of human Abeta42 secreted into the culture medium are measured using a sensitive, sandwich ELISA kit. Concurrently, cell viability is measured using an MTT or CellTiter-Glo assay. The EC50 for Abeta42 reduction is calculated.
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| Animal Protocol |
No specific in vivo protocol was found. A typical in vivo study for gamma-secretase inhibitors would use a mouse model of amyloidosis (e.g., Tg2576 or APP/PS1 transgenic mice). (9R)-RO7185876 would be formulated in a suitable vehicle (e.g., 2% DMSO, 5% Kolliphor HS 15, 93% saline) and administered to mice (e.g., 3-30 mg/kg, oral or IP) once daily for 14 days. At the end of the study, brain tissue is harvested, and Abeta40 and Abeta42 levels are measured by ELISA. Pharmacodynamic effects may be assessed by immunohistochemistry for Abeta plaques.
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| ADME/Pharmacokinetics |
No PK data was found for (9R)-RO7185876. As a small molecule designed for central nervous system (CNS) penetration, it is expected to have moderate oral bioavailability, a half-life suitable for once or twice daily dosing, and the ability to cross the blood-brain barrier. Its brain-to-plasma ratio would be a critical parameter in its evaluation.
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| Toxicity/Toxicokinetics |
No toxicity data was found for (9R)-RO7185876. A well-known toxicity of gamma-secretase inhibitors is on-target, mechanism-based toxicity due to the inhibition of Notch signaling, which is critical for cell differentiation. This can lead to serious gastrointestinal toxicity and thymic atrophy. Any new gamma-secretase inhibitor must demonstrate selectivity for APP over Notch cleavage to improve the safety window.
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| References | |
| Additional Infomation |
(9R)-RO7185876 is a research-grade compound for non-clinical use. Its CAS number is 2226077-86-5, molecular formula is C25H28F3N7, and molecular weight is 483.53. It is a selective inhibitor of gamma-secretase and a crucial tool for research into the role of Abeta42 in Alzheimer's disease and cerebral amyloid angiopathy. This product is not for human therapeutic use and is intended for laboratory research only. Each product in one row, fields tab-separated.
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| Molecular Formula |
C25H28F3N7
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|---|---|
| Molecular Weight |
483.53
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| CAS # |
2226077-86-5
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| Related CAS # |
RO7185876
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| Appearance |
Typically exists as solids at room temperature
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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 (~206.81 mM; with ultrasonication (<60°C))
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (10.34 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 50.0 mg/mL clear DMSO stock solution and add it to 900 μL of 20% SBE-β-CD saline solution and mix well. 2 g SBE-β-CD (sulfobutyl ether β-cyclodextrin) powder is diluted to 10 mL of saline and completely dissolved until clear and transparent. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0681 mL | 10.3406 mL | 20.6812 mL | |
| 5 mM | 0.4136 mL | 2.0681 mL | 4.1362 mL | |
| 10 mM | 0.2068 mL | 1.0341 mL | 2.0681 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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