PSI-6130 (R-1656) is a novel, potent and selective inhibitor of HCV NS5B polymerase which inhibits HCV replication with a mean IC50 of 0.6 μM. PSI-6130 is a cytidine analogue with potent and selective anti-hepatitis C virus (HCV) activity in the subgenomic HCV replicon assay, 90% effective concentration (EC90)=4.6 +/- 2.0 microM. The spectrum of activity and cytotoxicity profile of PSI-6130 was evaluated against a diverse panel of viruses and cell types, and against two additional HCV-1b replicons.
Physicochemical Properties
| Molecular Formula | C10H14N3O4F |
| Molecular Weight | 259.23426 |
| Exact Mass | 259.096 |
| Elemental Analysis | C, 46.33; H, 5.44; F, 7.33; N, 16.21; O, 24.69 |
| CAS # | 817204-33-4 |
| PubChem CID | 6481236 |
| Appearance | White to off-white solid powder |
| Density | 1.7±0.1 g/cm3 |
| Boiling Point | 482.4±55.0 °C at 760 mmHg |
| Flash Point | 245.5±31.5 °C |
| Vapour Pressure | 0.0±2.7 mmHg at 25°C |
| Index of Refraction | 1.653 |
| LogP | -0.72 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 2 |
| Heavy Atom Count | 18 |
| Complexity | 427 |
| Defined Atom Stereocenter Count | 4 |
| SMILES | C[C@]1([C@H](O)[C@@H](CO)O[C@H]1N1C=CC(N)=NC1=O)F |
| InChi Key | NYPIRLYMDJMKGW-UZRKRJFESA-N |
| InChi Code | InChI=1S/C10H14FN3O4/c1-10(11)7(16)5(4-15)18-8(10)14-3-2-6(12)13-9(14)17/h2-3,5,7-8,15-16H,4H2,1H3,(H2,12,13,17)/t5-,7-,8-,10+/m1/s1 |
| Chemical Name | 4-amino-1-((2R,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one |
| Synonyms | PSI-6130; PSI-6130; PSI-6130; R 1656; R-1656; R1656. |
| 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
| Targets | HCV replication(IC50= 0.6 μM) |
| ln Vitro | Strong and targeted inhibitory activity of PSI-6130 is shown against HCV RNA replication mediated by the NS5B polymerase. With mean EC50 values of 0.51 and 0.30 μM, respectively, PSI-6130 inhibits the subgenomic RNA replication of HCV GT-1b (Con1 strain) and GT-1a (H77 strain). At an EC50 of 0.51 μM, PSI-6130 inhibits 40% of human serum[1]. With a mean IC50 of 0.6 μM, PSI-6130 inhibits HCV replication, while PSI-6130-TP inhibits HCV replicase with a mean IC50 of 0.34 μM. With an IC50 of 0.13 μM and a Ki of 0.023 μM, PSI-6130-TP inhibits recombinant HCV Con1 NS5B on a heteropolymeric RNA template derived from the 3′-end of the HCV genome[2]. |
| Enzyme Assay | Using a complement strand of internal ribosomal entry site (cIRES) RNA template, the incorporation of radiolabeled NMP into acid-insoluble RNA products is used to measure the potency of compounds in inhibiting the RdRp activity of recombinant NS5B570-BK, NS5B570-Con1, and NS5B570-H77 proteins. In summary, 200 nM in vitro-transcribed cIRES RNA template, 1 μCi of tritiated UTP (42 Ci/mmol), 500 μM ATP, 500 μM GTP, 1 μM CTP, 1× TMDN buffer (40 mM Tris-HCl [pH 8.0], 4 mM MgCl2, 4 mM dithiothreitol, 40 mM NaCl), and 200 nM enzyme are used to determine 50% inhibitory concentration (IC50). Under the conditions of the GT-1b assay, compounds are tested for their ability to inhibit the RdRp activity of NS5B570-S282T-Con1; NS5B570-BK and NS5B570-Con1 enzymes are used as controls. 50 μL is the final reaction volume for all assay settings. There is a final 10% dimethyl sulfoxide in every reaction. Values Km and Ki are measured. |
| References |
[1]. Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479. Antimicrob Agents Chemother. 2008 Dec;52(12):4356-69. [2]. Characterization of the metabolic activation of hepatitis C virus nucleoside inhibitor beta-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) and identification of a novel active 5'-triphosphate species. J Biol Chem. 2007 Oct 12;282(41):298 |
Solubility Data
| Solubility (In Vitro) | DMSO : ~25 mg/mL (~96.44 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.64 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 (9.64 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 (9.64 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: 10% DMSO+40% PEG300+5% Tween-80+45% Saline: ≥ 2.5 mg/mL (9.64 mM) (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.8576 mL | 19.2879 mL | 38.5758 mL | |
| 5 mM | 0.7715 mL | 3.8576 mL | 7.7152 mL | |
| 10 mM | 0.3858 mL | 1.9288 mL | 3.8576 mL |