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| 10mg |
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| 100mg |
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| Targets |
HCV NS5B polymerase
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| ln Vitro |
PSI-6130 is an analogue of cytidine. Mericitabine (RG 7128; R-7128) is an oral prodrug of PSI-6130. According to preclinical data, PSI-6130 exhibits an EC90 value in the HCV replicon test of 4.6±2 μM. Mericitabine (RG 7128; R-7128) has little cytotoxicity, doesn't damage mitochondrial DNA, and is very selective for HCV. Cellular kinases phosphorylate PSI-6130, resulting in the production of an active 5'-triphosphate metabolite that inhibits HCV's NS5B RNA polymerase. Mecitabine (RG 7128; R-7128) has a notable anti-HCV-1 effectiveness and a comparatively acceptable safety profile [2]. Mericitabine is a novel type of nucleoside polymerase inhibitor (NPI) that needs to be absorbed inside the cells and phosphorylated twice to produce two active triphosphates. Oral cytidine nucleoside analog prodrug meretibine (RG 7128; R-7128) has strong antiviral activity against HCV polymerase in all HCV genotypes [3].
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| ln Vivo |
Mericitabine (RG7128) is a nucleoside polymerase inhibitor (NPI), which requires intracellular uptake and phosphorylation to two active triphosphates. Mathematical modeling has provided important insights for characterizing hepatitis C virus (HCV) RNA decline and estimating in vivo effectiveness of antiviral agents; however, it has not been used to characterize viral kinetics with NPIs. HCV RNA was frequently measured in 32 treatment-experienced patients infected with HCV genotype 1 during and after mericitabine monotherapy for 14 days with 750 mg or 1500 mg administered once (qd) or twice daily (bid). The initial decline of HCV RNA was typically slower than with interferon-α or protease inhibitors, and 12 patients presented a novel pattern of HCV RNA kinetics characterized by a monophasic viral decline. Viral kinetics could be well fitted by assuming that the effectiveness in blocking viral production gradually increased over time to reach its final value, ε(2), consistent with previous accumulation time estimates of intracellular triphosphates. ε(2) was high with bid dosing (mean 750 mg and 1500 mg: 98.0% and 99.8%, respectively; P = 0.018) and significantly higher than in patients treated qd (mean qd versus bid: 90% versus 99%, P < 10(-7)). Virus rebounded rapidly upon drug discontinuation, which was attributed to the elimination of active drug and the subsequent decline of drug effectiveness, with mean t(1/2) = 13.9 hours in the bid regimens[3].
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| Enzyme Assay |
Mericitabine (RG7128) is an oral cytidine nucleoside analog prodrug that exhibited strong antiviral effectiveness against the HCV polymerase across all HCV genotypes (9–11), with no evidence of resistance reported in patients treated with mericitabine monotherapy for 14 days (12). Upon entering the hepatocyte, mericitabine is converted to a cytidine monophosphate, which is then further converted to both a cytidine and a uridine triphosphate. Both triphosphate forms are active, with the cytidine form predominating at least early following the initiation of treatment[3].
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| Animal Protocol |
Multiple oral doses of mericitabine were administered for 14 days to 32 HCV-infected patients, split into four cohorts (n=10 patients per cohort with 8 getting drug and 2 taking placebo) with regimens of 750-mg QD, 1500-mg QD, 750-mg BID and 1500-mg BID. Mean changes in HCV RNA per dosing group are displayed in Figure 1[3].
In the INFORM-1 study, 73 patients with chronic hepatitis C virus infection received mericitabine plus danoprevir for up to 13 days. Seventy-two patients experienced a continuous decline in HCV RNA levels during treatment, and of these patients, 14 had viral loads that remained >1,000 IU/ml by day 13 and 1 met the definition for viral breakthrough. In-depth NS5B and NS3/4A population and clonal sequencing studies and mericitabine and danoprevir drug susceptibility testing were performed to assess the variability and quasispecies dynamics before and upon monotherapy or dual therapy. Sequence analysis of the viral quasispecies indicated that the mericitabine resistance mutation S282T was not present at baseline, nor was it selected (even at a low level) during treatment. Protease inhibitor resistance mutations, either as predominant or as minority species, were detected in 18 patients at baseline. No enrichment of minority protease inhibitor-resistant variants present at baseline was observed during treatment; viral population samples were fully susceptible to mericitabine and/or danoprevir, despite the presence within their quasispecies of minority variants confirmed to have reduced susceptibility to danoprevir or other protease inhibitors. It was also observed that certain NS3 amino acid substitutions affected protease inhibitor drug susceptibility in a compound-specific manner and varied with the genetic context. In summary, the slower kinetics of viral load decline observed in some patients was not due to the selection of danoprevir or mericitabine resistance during treatment. Over 2 weeks' therapy, mericitabine suppressed the selection of danoprevir resistance, results that could differ upon longer treatment periods.[1] |
| References |
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| Additional Infomation |
Mericitabine has been investigated for the treatment of Hepatitis C, Chronic. Mericitabine is a polymerase inhibitor being developed for the treatment of chronic hepatitis C. Mericitabine is a prodrug of PSI-6130, which demonstrated excellent potency in preclinical studies. PSI-6130 is a pyrimidine nucleoside analog inhibitor of HCV RNA polymerase, an enzyme that is necessary for hepatitis C viral replication.
Mericitabine is an orally available prodrug of PSI-6130 which is a selective cytidine nucleoside analogue and non-cytotoxic hepatitis C virus (HCV) polymerase inhibitor. After intracellular uptake, mericitabine is phosphorylated into two active triphosphate metabolites, which disable HCV RNA-dependent RNA polymerase (non-structural protein 5B; NS5B) upon binding. This results in the blockage of viral HCV RNA production and thus viral replication. This agent has a high barrier to resistance, however, a substitution mutation (S282T) on HCV NS5B impairs mericitabine's activity significantly. |
| Molecular Formula |
C18H26FN3O6
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|---|---|
| Molecular Weight |
399.4194
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| Exact Mass |
399.181
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| Elemental Analysis |
C, 54.13; H, 6.56; F, 4.76; N, 10.52; O, 24.03
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| CAS # |
940908-79-2
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| PubChem CID |
16122663
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| Appearance |
White to off-white solid powder
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| LogP |
1.56
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
28
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| Complexity |
707
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| Defined Atom Stereocenter Count |
4
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| SMILES |
CC(C)C(=O)OC[C@@H]1[C@H]([C@@]([C@@H](O1)N2C=CC(=NC2=O)N)(C)F)OC(=O)C(C)C
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| InChi Key |
MLESJYFEMSJZLZ-MAAOGQSESA-N
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| InChi Code |
InChI=1S/C18H26FN3O6/c1-9(2)14(23)26-8-11-13(28-15(24)10(3)4)18(5,19)16(27-11)22-7-6-12(20)21-17(22)25/h6-7,9-11,13,16H,8H2,1-5H3,(H2,20,21,25)/t11-,13-,16-,18-/m1/s1
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| Chemical Name |
(2R,3R,4R,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-4-fluoro-2-((isobutyryloxy)methyl)-4-methyltetrahydrofuran-3-yl isobutyrate
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| Synonyms |
RG7128; RG-7128; RG 7128; R-7128; R7128; R 7128; PSI 6130 diisobutyrate; PSI 6130 diisobutyrate; RO-5024048; 3',5'-Diisobutyryl PSI 6130; 3',5'-Diisobutyryl PSI 6130; Mericitabine.
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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 (~250.37 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.26 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 (6.26 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 (6.26 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 | 2.5036 mL | 12.5182 mL | 25.0363 mL | |
| 5 mM | 0.5007 mL | 2.5036 mL | 5.0073 mL | |
| 10 mM | 0.2504 mL | 1.2518 mL | 2.5036 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01482403 | COMPLETED | Drug: Copegus Drug: Copegus Drug: Pegasys |
Hepatitis C, Chronic | Hoffmann-La Roche | 2011-11 | Phase 2 |
| NCT01482390 | COMPLETED | Drug: Ribavirin Drug: Mericitabine Drug: Peginterferon Alfa-2a |
Hepatitis C | Hoffmann-La Roche | 2011-11-30 | Phase 2 |
| NCT01168856 | TERMINATEDWITH RESULTS | Hepatitis C, Chronic | Hoffmann-La Roche | 2010-09 |
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