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| 1mg |
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| 5mg |
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| 10mg |
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| 100mg |
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| Targets |
Inosine monophosphate dehydrogenase (IMPDH), specifically IMPDH type I and type II isoforms. IMPDH catalyzes the conversion of inosine monophosphate (IMP) to xanthine monophosphate (XMP), the rate-limiting step in de novo guanine nucleotide biosynthesis. Lymphocytes depend on this de novo synthesis pathway for proliferation, making IMPDH an attractive target for immunosuppression and antiviral therapy. Merimepodib is a non-competitive inhibitor of IMPDH.
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| ln Vitro |
Merimepodib potently inhibits IMPDH with IC50 values in the low nanomolar range (typically 5-15 nM for the active isomer). By blocking de novo guanine nucleotide synthesis, it depletes intracellular GTP and dGTP pools, inhibiting DNA synthesis and lymphocyte proliferation. The compound shows activity against hepatitis C virus (HCV) and other RNA and DNA viruses in cell-based assays. The (R)-enantiomer is the more active isomer compared to the (S)-enantiomer.
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| ln Vivo |
In vivo, Merimepodib has been evaluated in animal models of viral infection and autoimmune diseases. In the HCV replicon system (although HCV does not replicate efficiently in small animals, chimeric mouse models with humanized livers were used), Merimepodib demonstrated antiviral activity. The compound was also studied in organ transplant models as an immunosuppressant, showing prolongation of graft survival. (R)-Merimepodib is the active isomer used for pharmacological studies.
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| Enzyme Assay |
For IMPDH enzyme activity assays, recombinant human IMPDH type II is incubated with IMP (substrate), NAD+ (cofactor), and varying concentrations of test compound in assay buffer (50 mM Tris-Cl, pH 8.0, 100 mM KCl, 3 mM EDTA, 1 mM DTT) at 37degC for 30-60 minutes. The reaction is quenched, and NADH production (which is proportional to XMP formation) is measured spectrophotometrically at 340 nm. IC50 values are calculated from dose-response curves. Alternative assay: detection of XMP by HPLC or LC-MS.
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| Cell Assay |
For lymphocyte proliferation assays, human peripheral blood mononuclear cells (PBMCs) or purified T cells are isolated and stimulated with phytohemagglutinin (PHA, 5 ug/mL) or anti-CD3/anti-CD28 antibodies in the presence of varying concentrations of Merimepodib (0.1 nM to 10 uM) for 48-72 hours. Cell proliferation is measured by [3H]-thymidine incorporation or CFSE dilution by flow cytometry. For antiviral activity, HCV replicon-containing Huh-7 cells are treated with Merimepodib for 72 hours, and HCV RNA is quantified by qRT-PCR.
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| Animal Protocol |
For in vivo immunosuppression studies, rodent models of allograft transplantation (e.g., rat heterotopic heart transplantation) are used. Recipient rats receive Merimepodib orally at doses of 10-100 mg/kg/day starting on the day of transplantation. Graft survival is monitored daily by palpation of heart beats. Rejection is defined as the cessation of palpable heartbeat. Graft tissue is collected for histological analysis (H&E staining) to assess rejection severity. For autoimmune models, Merimepodib is tested in models of rheumatoid arthritis (collagen-induced arthritis, CIA).
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| ADME/Pharmacokinetics |
(R)-Merimepodib is orally bioavailable. In preclinical species, Merimepodib has moderate oral bioavailability (30-60%) and a half-life of 2-6 hours. The compound is metabolized primarily by CYP3A4 in the liver, with the major circulating metabolite being an inactive glucuronide conjugate. Plasma protein binding is high (>90%). Urinary excretion is the primary route of elimination, mainly as metabolites. Food intake can affect absorption; administration with a high-fat meal may reduce Cmax.
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| Toxicity/Toxicokinetics |
In animal toxicology studies, Merimepodib was generally well-tolerated at therapeutic doses. The primary toxicities observed at higher doses were related to IMPDH inhibition and included mild to moderate gastrointestinal disturbances (nausea, diarrhea) and reversible hematologic changes (mild leukopenia, thrombocytopenia). In clinical trials, the most common adverse events were nausea, diarrhea, and headache. No significant hepatotoxicity, nephrotoxicity, or serious infections were reported. No genotoxicity or carcinogenicity was observed.
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| References |
[1]. Jain J, et al. VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent. J Pharm Sci. 2001 May;90(5):625-37.
[2]. Decker CJ, et al. The novel IMPDH inhibitor VX-497 prolongs skin graft survival and improves graft versus host disease in mice. Drugs Exp Clin Res. 2001;27(3):89-95. [3]. Markland W, et al. Broad-spectrum antiviral activity of the IMP dehydrogenase inhibitor VX-497: a comparison with ribavirin and demonstration of antiviral additivity with alpha interferon. Antimicrob Agents Chemother. 2000 Apr;44(4):859-66. |
| Additional Infomation |
Merimepodib (VX-497) was developed by Vertex Pharmaceuticals as an IMPDH inhibitor for the treatment of hepatitis C virus (HCV) infection. In a Phase 2 clinical trial, the combination of Merimepodib plus pegylated interferon and ribavirin showed antiviral activity and was generally well-tolerated, though its further development for HCV may have been deprioritized following the approval of more effective direct-acting antivirals (DAAs). The compound has also been investigated for other viral infections and for immunosuppression in transplantation. This (R)-enantiomer is the active isomer used as a research tool. The product is for research use only and is not FDA-approved.
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| Molecular Formula |
C23H24N4O6
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| Molecular Weight |
452.46
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| Related CAS # |
Merimepodib;198821-22-6
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| Appearance |
Typically exists as solid 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) |
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 | 2.2101 mL | 11.0507 mL | 22.1014 mL | |
| 5 mM | 0.4420 mL | 2.2101 mL | 4.4203 mL | |
| 10 mM | 0.2210 mL | 1.1051 mL | 2.2101 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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