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| Targets |
Methionyl-tRNA synthetase (MetRS) of Clostridioides difficile. MetRS is an essential enzyme in protein synthesis that catalyzes the attachment of methionine to its cognate tRNA. Inhibition of MetRS leads to depletion of charged tRNA^Met, resulting in inhibition of protein synthesis and bacterial cell death. REP3123 selectively inhibits C. difficile MetRS without significantly affecting human mitochondrial MetRS.
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| ln Vitro |
In vitro, REP3123 demonstrates potent antibacterial activity against Clostridioides difficile with low minimum inhibitory concentrations (MICs). The compound also shows activity against aerobic Gram-positive bacteria but has little activity against Gram-negative bacteria. Its mechanism of action as a MetRS inhibitor has been confirmed in enzymatic assays. REP3123 inhibits C. difficile toxin production and spore formation.
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| ln Vivo |
In vivo, REP3123 has shown promise in treating Clostridioides difficile infections in preclinical models. The compound is orally bioavailable and effective in reducing bacterial burden and toxin levels in animal models of CDI. Its selective inhibition of C. difficile MetRS minimizes effects on the host and normal gut microbiota, making it a promising candidate for CDI treatment.
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| Enzyme Assay |
Cell-free enzyme assays for REP3123 use recombinant C. difficile methionyl-tRNA synthetase (MetRS). The enzyme is incubated with ATP, methionine, and tRNA^Met in the presence of varying concentrations of REP3123 (0.001-100 μM). Aminoacylation of tRNA is measured by incorporation of radiolabeled [³⁵S]-methionine or by a colorimetric/fluorescent assay for ATP consumption. IC50 values are calculated from dose-response curves. Selectivity is assessed by testing the compound against human mitochondrial MetRS.
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| Cell Assay |
Cellular antibacterial assays for REP3123 are performed using C. difficile strains (e.g., ATCC 43255 or clinical isolates) cultured in appropriate anaerobic media. Bacteria are inoculated in broth and treated with REP3123 at concentrations ranging from 0.001-100 μg/mL. After 24-48 hours of anaerobic incubation, minimum inhibitory concentrations (MICs) are determined by broth microdilution according to CLSI guidelines. Time-kill assays are performed to assess bactericidal activity. Spore formation and toxin production are measured by ELISA or cell-based cytotoxicity assays.
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| Animal Protocol |
In vivo efficacy studies are conducted in mouse or hamster models of C. difficile infection (CDI). Animals are infected with C. difficile after antibiotic pretreatment to disrupt the normal gut microbiota. REP3123 is administered orally at doses typically ranging from 1-50 mg/kg, once or twice daily. Disease progression is monitored by measuring survival, weight loss, diarrhea severity, and bacterial burden in feces. Toxin levels in feces are measured by ELISA. Histopathological assessment of the colon is performed to evaluate tissue damage.
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| ADME/Pharmacokinetics |
Pharmacokinetic studies of REP3123 demonstrate that the compound is orally bioavailable. PK parameters such as Cmax, Tmax, AUC, half-life, and oral bioavailability are determined in rodents and other preclinical species. The compound's distribution to the gastrointestinal tract, the site of C. difficile infection, is of particular interest. Metabolic stability is assessed using liver microsome or hepatocyte incubation studies. The compound's favorable PK properties support oral dosing for CDI treatment.
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| Toxicity/Toxicokinetics |
Toxicology studies of REP3123 were conducted as part of its preclinical development program. As a bacterial MetRS inhibitor with selectivity for C. difficile over human enzymes, the compound is expected to have a favorable safety profile. Standard toxicology studies (acute, subchronic, and chronic) in rodents and non-human primates would be required for clinical development. At research-grade doses used in animal models, the compound is generally well-tolerated.
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| Additional Infomation |
REP3123 Dihydrochloride (CRS3123) is a research compound being developed for the treatment of C. difficile infection (CDI). It is not an approved therapeutic agent. The compound is available from chemical suppliers for research purposes only. Its mechanism as a selective bacterial MetRS inhibitor makes it a promising candidate for CDI treatment with potential advantages over existing antibiotics, including reduced impact on the gut microbiota. The compound is typically stored at -20°C for long-term stability.
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| Molecular Formula |
C19H21BR2CL2N3O2S
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|---|---|
| Molecular Weight |
586.16
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| Exact Mass |
582.91
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| CAS # |
1013915-99-5
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| Related CAS # |
CRS3123;1013915-71-3
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| PubChem CID |
24762985
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
6.859
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
579
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| Defined Atom Stereocenter Count |
1
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| SMILES |
Cl.Cl.C(CN[C@@H]1CCOC2=C(C=C(C=C12)Br)Br)CNC1=CC(=O)C2SC=CC=2N1
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| InChi Key |
HZJABMYSJSDCBO-FMOMHUKBSA-N
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| InChi Code |
InChI=1S/C19H19Br2N3O2S.2ClH/c20-11-8-12-14(2-6-26-18(12)13(21)9-11)22-4-1-5-23-17-10-16(25)19-15(24-17)3-7-27-19;;/h3,7-10,14,22H,1-2,4-6H2,(H2,23,24,25);2*1H/t14-;;/m1../s1
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| Chemical Name |
5-[3-[[(4R)-6,8-dibromo-3,4-dihydro-2H-chromen-4-yl]amino]propylamino]-4H-thieno[3,2-b]pyridin-7-one;dihydrochloride
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| Synonyms |
REP 3123 Dihydrochloride; REP-3123 Dihydrochloride; CRS3123 2HCl
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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, avoid exposure to moisture. |
| 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 (~170.60 mM)
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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 | 1.7060 mL | 8.5301 mL | 17.0602 mL | |
| 5 mM | 0.3412 mL | 1.7060 mL | 3.4120 mL | |
| 10 mM | 0.1706 mL | 0.8530 mL | 1.7060 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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