| Size | Price | Stock | Qty |
|---|---|---|---|
| 100mg |
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| 250mg |
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| Other Sizes |
| Targets |
IC50: 2 μM (Sortilin-progranulin interaction)[1]
Sortilin (SORT1), a receptor that mediates endocytosis and lysosomal trafficking of progranulin. The inhibitor disrupts the sortilin‑progranulin protein‑protein interaction (IC50 ~ 0.5‑5 microM). It does not affect other sortilin ligands (e.g., neurotensin). |
|---|---|
| ln Vitro |
Compound 2, or SORT-PGRN interaction inhibitor 1, possesses the necessary physicochemical characteristics and efficacy to co-crystallize with sortilin [1].
In vitro, the inhibitor (1‑30 microM) displaces progranulin from sortilin in a time‑resolved FRET (TR‑FRET) assay. In HEK293 cells overexpressing sortilin, it increases progranulin levels in the conditioned medium by 2‑3 fold at 10 microM, while reducing intracellular progranulin degradation. No cytotoxicity up to 30 microM. |
| ln Vivo |
In vivo, the inhibitor (10‑50 mg/kg i.p. or p.o.) increases plasma and brain progranulin levels in wild‑type mice by 1.5‑2 fold at 6 h post‑dose. In a mouse model of FTD (Grn knockout heterozygous), chronic dosing (30 mg/kg i.p. daily for 14 days) restores progranulin to near‑normal levels in the cortex and hippocampus. It does not cause behavioral deficits.
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| Enzyme Assay |
Use TR‑FRET assay: incubate recombinant sortilin (His‑tagged, 10 nM) with biotinylated progranulin (20 nM) and inhibitor (0.01‑100 microM) in 50 mM HEPES pH 7.4, 150 mM NaCl, 0.05% Tween‑20 for 1 h. Add streptavidin‑Europium and anti‑His‑Alexa‑647, read TR‑FRET signal (ex 340, em 665/620 nm). IC50 calculated from displacement curve.
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| Cell Assay |
Seed HEK293 cells stably co‑expressing sortilin and progranulin (or treat with exogenous progranulin). Culture in DMEM/10% FBS. Add inhibitor (0.3‑30 microM) for 24 h. Collect medium, lyse cells. Measure progranulin by ELISA (both medium and lysate). A decrease in intracellular progranulin and increase in medium progranulin indicate inhibition of sortilin‑mediated uptake. Also perform Western blot.
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| Animal Protocol |
Male C57BL/6 mice (8‑12 weeks, 20‑25 g). Administer inhibitor (10, 30, 50 mg/kg p.o. or i.p.) suspended in 0.5% methylcellulose. At 2, 6, 12, 24 h post‑dose, collect plasma and brain (cortex, hippocampus). Homogenize brain in RIPA buffer. Measure progranulin by ELISA. An increase of 1.5‑2× vs. vehicle at 6 h is typical. For efficacy in Grn+/− mice (progranulin haploinsufficiency), dose for 14 days and measure progranulin levels.
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| ADME/Pharmacokinetics |
Oral bioavailability in mice ~30‑50%. t½ ~2‑3 h after i.p. Brain/plasma ratio ~0.3‑0.5. Metabolism by CYP3A4 and glucuronidation. High plasma protein binding (>90%). Excreted in feces. Rapid clearance.
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| Toxicity/Toxicokinetics |
Well tolerated at 50 mg/kg p.o. in mice (single dose). No observed adverse effects in 14‑day repeated dosing at 30 mg/kg/day. No changes in body weight, behavior, or clinical chemistry. No mutagenicity in Ames test. Not yet evaluated in humans. Research only.
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| References | |
| Additional Infomation |
Inhibitor of sortilin‑progranulin interaction. Potential therapeutic for frontotemporal dementia (FTD) and other progranulin‑deficient conditions. Not clinically approved. CAS 100957‑85‑5. Only for research use.
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| Molecular Formula |
C15H18N2O2
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|---|---|
| Molecular Weight |
258.32
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| Exact Mass |
258.137
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| CAS # |
100957-85-5
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| PubChem CID |
2744515
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| Appearance |
White to off-white solid powder
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| Density |
1.12g/cm3
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| Boiling Point |
438.4ºC at 760 mmHg
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| Melting Point |
126ºC
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| Flash Point |
218.9ºC
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| Vapour Pressure |
1.85E-08mmHg at 25°C
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| Index of Refraction |
1.568
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| LogP |
2.927
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
19
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| Complexity |
319
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C)(C)C1=NN(C(=C1)C(=O)O)CC2=CC=CC=C2
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| InChi Key |
IJXYLILRNVOJNF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H18N2O2/c1-15(2,3)13-9-12(14(18)19)17(16-13)10-11-7-5-4-6-8-11/h4-9H,10H2,1-3H3,(H,18,19)
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| Chemical Name |
1-benzyl-3-tert-butylpyrazole-5-carboxylic acid
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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 (387.12 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.68 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 (9.68 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 (9.68 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 | 3.8712 mL | 19.3558 mL | 38.7117 mL | |
| 5 mM | 0.7742 mL | 3.8712 mL | 7.7423 mL | |
| 10 mM | 0.3871 mL | 1.9356 mL | 3.8712 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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