| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| 5mg |
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| Other Sizes |
| Targets |
human Cathepsin S 0.4 nM (IC50) murine Cathepsin S 0.5 nM (IC50)
Cathepsin S |
|---|---|
| ln Vitro |
In mouse (A20) or human (RAJI) cell lines, RO5461111 (16 h) is cytoactive and dramatically lowers splenic dendritic cell activation, as well as the subsequent growth and activation of CD4 T cells and CD4/CD8 double negative T cells[1].
RO5461111 is a potent Cathepsin S antagonist with IC50 values of 0.4 nM (human Cathepsin S) and 0.5 nM (murine Cathepsin S). It effectively inhibits the activation of antigen-specific T cells and B cells. In vitro, RO5461111 (16 h) reduces the activation of spleen dendritic cells and subsequent expansion of CD4 T cells. |
| ln Vivo |
Following sheep IgG immunization, RO5461111 (0.1–100 mg/kg; oral; single dosage) prevents T cell priming and anti-sheep IgG in BALB/c mice[1]. In MRL-Fas(lpr) mice, RO5461111 (1.31 mg/mouse or 30 mg/kg; oral; 8 weeks) decreases hypergammaglobulinemia, lupus autoantibody product F, and disturbs the germinal center (e.g., diminishes CXCL12 expression). Moreover, RO5461111 can lessen lupus nephritis and lessen lung inflammation[1].
In vivo, RO5461111 (0.1-100 mg/kg, oral, single dose) inhibits T cell priming and anti-sheep IgG response in BALB/c mice. At 1.31 mg/mouse (or 30 mg/kg, oral, 8 weeks), it disrupts germinal center formation, reduces hypergammaglobulinemia, and decreases lupus autoantibodies in MRL-Fas(lpr) mice. It also ameliorates pulmonary inflammation and lupus nephritis. |
| Enzyme Assay |
Cathepsin S activity is measured using a fluorogenic substrate such as Z-Val-Val-Arg-AMC. The compound is pre-incubated with the enzyme in an assay buffer (e.g., 100 mM sodium phosphate, pH 6.5, 5 mM EDTA, 5 mM DTT) at 37degC for 10 minutes. The reaction is initiated by adding the substrate, and fluorescence is monitored (Ex/Em=380/460 nm) to calculate IC50.
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| Cell Assay |
General cellular protocols for studying cathepsin S involve using RAJI (human B cell) or A20 (murine B cell) cell lines. Cells are treated with RO5461111 for 16 hours, and antigen presentation to T cells is assessed. Alternatively, mouse spleen cells are cultured with antigen (e.g., sheep IgG) and the compound, and T cell proliferation is measured by 3H-thymidine incorporation.
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| Animal Protocol |
Animal/Disease Models: Female MRL-Fas(lpr) mice (12weeks old; with proteinuria/serum creatinine levels up)[1]
Doses: 262.5 mg/kg chow; or 5 mg/mouse with 1.31 mg/mouse Route of Administration: Oral gavage; 8 weeks Experimental Results: decreased the activation and expansion of spleen dendritic cells, CD4, double-negative T cells and plasma cells. decreased plasma levels of IL-10 and TNF-α. A mouse model of systemic lupus erythematosus (SLE) using MRL-Fas(lpr) mice is standard. RO5461111 is administered orally at 1.31 mg/mouse for 8 weeks. Endpoints include measurement of autoantibodies (anti-dsDNA) by ELISA, assessment of proteinuria and kidney histopathology for lupus nephritis, and measurement of cytokine levels (IL-10, TNF-alpha) in plasma. |
| ADME/Pharmacokinetics |
RO5461111 has a molecular weight of 614.56. It is orally active, indicating good oral bioavailability. Pharmacokinetic parameters in rodents likely include a moderate half-life and good plasma exposure. Detailed PK parameters (e.g., Cmax, Tmax, AUC, t1/2) for this compound have been reported in the primary literature.
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| Toxicity/Toxicokinetics |
RO5461111 is considered a research compound with preclinical safety data. Specific toxicity data is not publicly available, but as a small molecule inhibitor, safety pharmacology and toxicology studies would be required for clinical development. No significant adverse effects were reported in the described mouse studies at therapeutic doses.
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| References |
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| Additional Infomation |
RO5461111 is a research compound that functions as a selective Cathepsin S antagonist. It is used as a tool to study the role of Cathepsin S in autoimmune diseases such as systemic lupus erythematosus (SLE) and in inflammatory conditions. It has not yet advanced to human clinical trials.
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| Molecular Formula |
C27H24F6N4O4S
|
|---|---|
| Molecular Weight |
614.559286117554
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| Exact Mass |
614.142
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| CAS # |
1252637-46-9
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| PubChem CID |
59543651
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| Appearance |
White to off-white solid powder
|
| LogP |
3.6
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
12
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
42
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| Complexity |
1250
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| Defined Atom Stereocenter Count |
2
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| SMILES |
CC1=NC=CC(=C1)C2=CC(=C(C=C2)S(=O)(=O)[C@@H]3C[C@H](N(C3)C(=O)C4(CC4)C(F)(F)F)C(=O)NC5(CC5)C#N)C(F)(F)F
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| InChi Key |
CDBYZSRUFZXRLK-QUCCMNQESA-N
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| InChi Code |
InChI=1S/C27H24F6N4O4S/c1-15-10-17(4-9-35-15)16-2-3-21(19(11-16)26(28,29)30)42(40,41)18-12-20(22(38)36-24(14-34)5-6-24)37(13-18)23(39)25(7-8-25)27(31,32)33/h2-4,9-11,18,20H,5-8,12-13H2,1H3,(H,36,38)/t18-,20+/m1/s1
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| Chemical Name |
(2S,4R)-N-(1-cyanocyclopropyl)-4-[4-(2-methylpyridin-4-yl)-2-(trifluoromethyl)phenyl]sulfonyl-1-[1-(trifluoromethyl)cyclopropanecarbonyl]pyrrolidine-2-carboxamide
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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 (e.g. under nitrogen), avoid exposure to moisture and light. |
| 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 (162.72 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 1.67 mg/mL (2.72 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 16.7 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: ≥ 1.67 mg/mL (2.72 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6272 mL | 8.1359 mL | 16.2718 mL | |
| 5 mM | 0.3254 mL | 1.6272 mL | 3.2544 mL | |
| 10 mM | 0.1627 mL | 0.8136 mL | 1.6272 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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