Merimepodib, formerly known as VX-497, is orally bioavailable IMPDH inhibitor, which inhibits the proliferation of primary human, mouse, rat, and dog lymphocytes at concentrations of approximately 100 nM. In vivo, orally bioavailable administration of VX-497 inhibits the primary IgM antibody response in a dose-dependent manner, with an ED(50) value of approximately 30-35 mg/kg in mice. Single daily dosing of VX-497 is observed to be as effective as twice-daily dosing in this model of immune activation. These studies demonstrate that VX-497 is a potent, specific, and reversible IMPDH inhibitor that selectively inhibits lymphocyte proliferation.
Physicochemical Properties
| Molecular Formula | C23H24N4O6 |
| Molecular Weight | 452.46 |
| Exact Mass | 452.169 |
| Elemental Analysis | C, 61.05; H, 5.35; N, 12.38; O, 21.22 |
| CAS # | 198821-22-6 |
| Related CAS # | (R)-Merimepodib |
| PubChem CID | 153241 |
| Appearance | white solid powder |
| Density | 1.4±0.1 g/cm3 |
| Boiling Point | 571.4±50.0 °C at 760 mmHg |
| Flash Point | 299.4±30.1 °C |
| Vapour Pressure | 0.0±1.6 mmHg at 25°C |
| Index of Refraction | 1.632 |
| LogP | 2.05 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 7 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 33 |
| Complexity | 652 |
| Defined Atom Stereocenter Count | 1 |
| SMILES | O1C([H])([H])C([H])([H])[C@@]([H])(C1([H])[H])OC(N([H])C([H])([H])C1C([H])=C([H])C([H])=C(C=1[H])N([H])C(N([H])C1C([H])=C([H])C(C2=C([H])N=C([H])O2)=C(C=1[H])OC([H])([H])[H])=O)=O |
| InChi Key | BPUGFODGPKTDW-SFHVURJKSA-N |
| InChi Code | InChI=1S/C23H24N4O6/c1-30-20-10-17(5-6-19(20)21-12-24-14-32-21)27-22(28)26-16-4-2-3-15(9-16)11-25-23(29)33-18-7-8-31-13-18/h2-6,9-10,12,14,18H,7-8,11,13H2,1H3,(H,25,29)(H2,26,27,28)/t18-/m0/s1 |
| Chemical Name | (S)-tetrahydrofuran-3-yl 3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate |
| Synonyms | Merimepodib; VX497; VX-497; VX 497; MMP; VI21497; VI-21497; VI 21497 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| ln Vitro | Within 48 hours of starting, VX-497's anti-proliferative effects on cells are reversed [1]. With an IC50 range from 6 to 19 μM, VX-497 exhibits moderate antiviral efficacy against Group II viruses, such as HSV-1, parainfluenza-3 virus, BVDV, VEEV, and dengue virus. With an IC50 of 380 nM, a corresponding CC50 of 5.2 μM, and a therapeutic index of 14, VX-497 is 100 times more effective [2]. |
| ln Vivo | Primary IgM antibody responses are dose-dependently inhibited by port VX-497, which has an ED50 value of about 30-35 mg/kg in mice. It was found that a single daily dose of variable VX-497 was just as effective as twice daily dosing in this immune activation paradigm [1]. Allogeneic F1 mice given a vehicle treatment develop GVHD, and VX-497 treatment greatly reduces all illness symptoms. In animals treated with VX-497, the 2.9-fold rise in kidney weight observed in transplanted mice was lowered to a 1.6-fold increase. The native group's serum IFN-γ levels jumped 54-fold, whereas the VX-497-treated animals' levels increased 7.4-fold [3]. |
| References |
[1]. VX-497: a novel, selective IMPDH inhibitor and immunosuppressive agent. J Pharm Sci. 2001 May;90(5):625-37. [2]. 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. [3]. 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. |
| Additional Infomation |
Merimepodib (VX-497) is a novel noncompetitive inhibitor of IMPDH. Merimepodib is orally bioavailable and inhibits the proliferation of primary human, mouse, rat, and dog lymphocytes at concentrations of approximately 100 nM. Merimepodib is an inosine monophosphate dehydrogenase (IMPDH) inhibitor with activity against hepatitis C virus (HCV). IMPDH catalyzes the rate-limiting step in the de novo synthesis of guanine nucleotides, and treatment with merimepodib reduces the intracellular guanine nucleotide levels that are required for RNA and DNA synthesis, resulting in antiproliferative and antiviral effect. Drug Indication For the treatment of hepatitis C virus (HCV) infection. Mechanism of Action Merimepodib is a orally active inhibitor of inosine monophospate dehydrogenase (IMPDH). IMPDH inhibition leads to a reduction in intracellular guanosine triphosphate (GTP), a molecule required for DNA and RNA synthesis. Pharmacodynamics Merimepodib, an oral drug, contains a novel inhibitor of inosine monophosphate dehydrogenase (IMPDH), an enzyme responsible for stimulating the production of lymphocytes. Merimepodib has the potential to exert direct antiviral activity, as well as affect the immune response by acting on lymphocyte migration and proliferation. Consequently, merimepodib may be an effective treatment for hepatitis C virus (HCV) infection, as the disease involves both viral proliferation and liver inflammation. |
Solubility Data
| Solubility (In Vitro) | DMSO : 31~90 mg/mL (68.51~198.91 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.53 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 (5.53 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.53 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 4: ≥ 2.5 mg/mL (5.53 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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. Solubility in Formulation 5: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (5.53 mM) (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 |