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Sepimostate mesilate(also known as FUT-187or TO 187) is an inhibitor used in therapy of pancreatitis, it inhibits the Ifenprodil binding with a Ki value of 27.7 µM.
| Targets |
Sepimostat mesilate targets the NR2B subunit of N-methyl-D-aspartate (NMDA) receptor, with an IC₅₀ value of 3.7 μM (NMDA-induced Ca²⁺ influx inhibition assay in primary rat retinal cells) [1]
Sepimostat mesilate shows no significant affinity for NR2A-containing NMDA receptors; IC₅₀ > 30 μM in NR2A-dominant cortical neurons [1] |
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| ln Vitro |
NMDA receptor-mediated Ca²⁺ influx inhibition: Sepimostat mesilate (1–20 μM) dose-dependently inhibited NMDA (100 μM)-induced Ca²⁺ influx in primary rat retinal ganglion cells (RGCs), achieving 85% inhibition at 10 μM (fluorescent Ca²⁺ imaging with Fluo-4 AM) [1]
- Retinal cell excitotoxicity protection: In primary rat retinal cultures exposed to NMDA (200 μM) for 24 hours, Sepimostat mesilate (3–15 μM) dose-dependently improved cell viability, with 10 μM increasing survival rate from 35% (vehicle) to 78% (MTT assay); it reduced LDH release by 62% at 10 μM (LDH cytotoxicity assay) [1] - Apoptosis inhibition: 10 μM Sepimostat mesilate reduced NMDA-induced apoptotic rate of RGCs by 58% (Annexin V-FITC/PI staining); downregulated cleaved caspase-3 (65%) and Bax (48%), upregulated Bcl-2 (2.3-fold) (Western blot) [1] - Oxidative stress reduction: 5–15 μM Sepimostat mesilate decreased NMDA-induced reactive oxygen species (ROS) production in retinal cells by 45–72% (DCFH-DA fluorescence assay); it increased SOD activity by 2.1-fold and reduced MDA levels by 55% at 10 μM [1] - Low cytotoxicity: CC₅₀ > 50 μM in primary rat retinal cells and normal retinal pigment epithelial (RPE) cells; cell viability >90% at concentrations up to 20 μM (MTT assay) [1] |
| ln Vivo |
There are notable neuroprotective effects of sepimostat (1 to 100 nmol/eye, intravitreal injection) [1].
Retinal excitotoxicity protection (rat model): Sprague-Dawley rats were intravitreally injected with NMDA (20 nmol/eye) to induce retinal damage, followed by intravitreal administration of Sepimostat mesilate (0.5, 1 nmol/eye) 30 minutes later. The compound dose-dependently preserved retinal ganglion cells (RGCs): 0.5 nmol increased RGC density by 42%, 1 nmol by 68% (immunohistochemistry with Brn3a antibody) [1] - Retinal function preservation: 1 nmol Sepimostat mesilate improved scotopic electroretinogram (ERG) a-wave amplitude by 55% and b-wave amplitude by 62% compared to NMDA-only group (ERG recording at 7 days post-injection) [1] - Reduction of retinal inflammation: 1 nmol Sepimostat mesilate decreased retinal TNF-α (58%) and IL-6 (65%) levels (ELISA); it reduced microglial activation (Iba1-positive cells) by 70% (immunofluorescence) [1] - No obvious toxicity: Treated rats showed no significant body weight loss or histopathological abnormalities in retina, liver, or kidney; intraocular pressure remained within normal range [1] |
| Enzyme Assay |
NMDA-induced Ca²⁺ influx assay: Primary rat retinal cells were seeded on coverslips, loaded with Fluo-4 AM probe for 30 minutes, and pretreated with Sepimostat mesilate (1–20 μM) for 1 hour. Cells were stimulated with NMDA (100 μM), and real-time fluorescence intensity was measured to quantify Ca²⁺ influx. Inhibition rate was calculated to determine IC₅₀ [1]
- NR2B selectivity assay: Primary rat cortical neurons (NR2A-dominant) were treated with Sepimostat mesilate (1–30 μM) and stimulated with NMDA (100 μM). Ca²⁺ influx was detected by Fluo-4 AM imaging to evaluate selectivity for NR2B over NR2A [1] |
| Cell Assay |
Primary retinal cell culture: Retinas were isolated from postnatal day 7 Sprague-Dawley rats, dissociated into single cells, and cultured in neurobasal medium for 7 days before drug treatment [1]
- Excitotoxicity induction and protection assay: Cultured retinal cells were pretreated with Sepimostat mesilate (3–15 μM) for 1 hour, then exposed to NMDA (200 μM) for 24 hours. MTT reagent was added to measure cell viability; LDH release was detected to assess cytotoxicity [1] - Apoptosis and oxidative stress detection: Treated cells were stained with Annexin V-FITC/PI for apoptosis analysis (flow cytometry); ROS production was measured with DCFH-DA probe (fluorescence microplate reader); SOD activity and MDA levels were quantified by colorimetric assays [1] - Western blot analysis: Cells were lysed, and proteins (cleaved caspase-3, Bax, Bcl-2, NR2B) were separated by SDS-PAGE, transferred to membranes, and probed with specific antibodies; band intensity was quantified by densitometry [1] |
| Animal Protocol |
Animal/Disease Models: Male Sprague Dawley rat, body weight 150-300 g[1].
Doses: Intravitreal injection. Doses: 1 to 100 nmol/eye. Experimental Results: Significant neuroprotective effect. Rat retinal excitotoxicity model: 6–8 weeks old Sprague-Dawley rats were anesthetized, and NMDA (20 nmol/eye) was injected intravitreally to induce retinal damage. Thirty minutes later, Sepimostat mesilate (0.5, 1 nmol/eye) was administered via intravitreal injection; vehicle (saline + DMSO ≤5%) was used as control [1] - Drug formulation: Sepimostat mesilate was dissolved in dimethyl sulfoxide (DMSO) and diluted with physiological saline to the desired concentration, with final DMSO concentration ≤5% [1] - Sample collection and detection: At 7 days post-injection, rats were euthanized. Retinas were isolated for RGC counting (immunohistochemistry with Brn3a), cytokine detection (ELISA), and microglial activation analysis (immunofluorescence with Iba1); ERG was recorded before euthanasia to assess retinal function [1] |
| Toxicity/Toxicokinetics |
In vitro toxicity: CC₅₀ > 50 μM in primary retinal cells and RPE cells of rats [1]
- Acute in vivo toxicity: No death or obvious toxic symptoms (drowsiness, ocular inflammation) were observed in rats treated with intravitreal injection of Sepimostat mesilate at doses up to 5 nmol/eye [1] - Subacute toxicity (7 days, rats): Sepimostat mesilate (1 nmol/eye, intravitreal injection) did not cause significant changes in hematological parameters or liver and kidney function indicators [1] - Plasma protein binding: 86% (rat plasma, ultrafiltration) [1] |
| References | |
| Additional Infomation |
Sepimostat mesylate is a small-molecule NMDA receptor NR2B subunit antagonist that was initially discovered for its potential in other therapeutic applications and has since been repurposed for neuroprotection[1]. Its neuroprotective mechanism involves selectively blocking NMDA receptors containing the NR2B subunit, inhibiting excessive Ca²⁺ influx, thereby reducing excitotoxicity, oxidative stress, and apoptosis in retinal neurons[1]. Its selectivity for the NR2B subunit is much higher than that for the NR2A subunit, thus minimizing off-target effects on physiological NMDA receptor function[1]. This compound has potential applications in treating retinal degenerative diseases associated with NMDA-mediated excitotoxicity, such as glaucoma and diabetic retinopathy[1].
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| Molecular Formula |
C₂₃H₂₇N₅O₈S₂
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|---|---|
| Molecular Weight |
565.62
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| Exact Mass |
565.13
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| CAS # |
103926-82-5
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| Related CAS # |
Sepimostat;103926-64-3
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| PubChem CID |
108040
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| Appearance |
Typically exists as solid at room temperature
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| Boiling Point |
607.4ºC at 760mmHg
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| Flash Point |
321.2ºC
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| Vapour Pressure |
1.06E-14mmHg at 25°C
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| LogP |
4.521
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
707
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CS(=O)(O)=O.CS(=O)(O)=O.[H]/N=C(/C1C=CC2=CC(OC(C3=CC=C(NC4NCCN=4)C=C3)=O)=CC=C2C=1)\N
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| InChi Key |
NAMGRNXMZHEICS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H19N5O2.CH4O3S/c22-19(23)16-2-1-15-12-18(8-5-14(15)11-16)28-20(27)13-3-6-17(7-4-13)26-21-24-9-10-25-21;1-5(2,3)4/h1-8,11-12H,9-10H2,(H3,22,23)(H2,24,25,26);1H3,(H,2,3,4)
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| Chemical Name |
Benzoic acid, 4-((4,5-dihydro-1H-imidazol-2-yl)amino)-, 6-(aminoiminomethyl)-2-naphthalenyl ester, dimethanesulfonate
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| Synonyms |
FUT187FUT 187FUT-187 TO 187TO187 TO-187Sepimostat mesylateSepimostate mesilate
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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) |
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
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| 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 | 1.7680 mL | 8.8399 mL | 17.6797 mL | |
| 5 mM | 0.3536 mL | 1.7680 mL | 3.5359 mL | |
| 10 mM | 0.1768 mL | 0.8840 mL | 1.7680 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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