PSI-6130

Inhibitor of HCV nucleoside polymerase,selective and effective CAS# 817204-33-4

PSI-6130

Catalog No. BCC1870----Order now to get a substantial discount!

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Chemical structure

PSI-6130

3D structure

Chemical Properties of PSI-6130

Cas No. 817204-33-4 SDF Download SDF
PubChem ID 6481236 Appearance Powder
Formula C10H14FN3O4 M.Wt 259.23
Type of Compound N/A Storage Desiccate at -20°C
Synonyms R 1656
Solubility DMSO : ≥ 50 mg/mL (192.88 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 4-amino-1-[(2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-yl]pyrimidin-2-one
SMILES CC1(C(C(OC1N2C=CC(=NC2=O)N)CO)O)F
Standard InChIKey NYPIRLYMDJMKGW-VPCXQMTMSA-N
Standard InChI 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
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of PSI-6130

DescriptionPSI-6130 is a potent and selective inhibitor of HCV NS5B polymerase
TargetsHepatitis C Virus Nucleoside    

Protocol

Kinase Assay [1]
The inhibition potency of compounds with respect to the RdRp activity of recombinant NS5B570-BK, NS5B570-Con1, and NS5B570-H77 proteins is determined by measuring the incorporation of radiolabeled NMP into acid-insoluble RNA products by use of a complement strand of internal ribosomal entry site (cIRES) RNA template. Briefly, 50% inhibitory concentration (IC50) determinations are carried out using 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. The inhibition potency of compounds with respect to the RdRp activity of NS5B570-S282T-Con1 is determined under GT-1b assay conditions as. NS5B570-BK and NS5B570-Con1 enzymes are used as controls. The final reaction volume is 50 μL under all assay conditions. All reactions contain a final 10% dimethyl sulfoxide. Km and Ki values are measured.

References:
[1]. Ali S, et al. 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]. Ma H, et al. 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):29812-20. Epub 2007 Aug 13.

PSI-6130 Dilution Calculator

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PSI-6130 Molarity Calculator

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Preparing Stock Solutions of PSI-6130

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 3.8576 mL 19.2879 mL 38.5758 mL 77.1516 mL 96.4395 mL
5 mM 0.7715 mL 3.8576 mL 7.7152 mL 15.4303 mL 19.2879 mL
10 mM 0.3858 mL 1.9288 mL 3.8576 mL 7.7152 mL 9.6439 mL
50 mM 0.0772 mL 0.3858 mL 0.7715 mL 1.543 mL 1.9288 mL
100 mM 0.0386 mL 0.1929 mL 0.3858 mL 0.7715 mL 0.9644 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on PSI-6130

PSI-6130 is a selective and effective inhibitor of hepatitis C virus (HCV) RNA replication with an EC50 of 0.46 μM. It is a potent nucleoside analog which incorporates into nascent RNA by the HCV NS5B polymerase and leads to chain termination. [1]
NS5B is a viral protein discovered in hepatitis c virus. It plays a significant role in the replication of HCV, which uses HCV’S viral positive RNA strand as the template and catalyzes the polymerization of rNTP during RNA replication. PSI-6130 is a nucleotide analog and it can be activated by converting into nucleotide triphosphate form, which can be an alternative substrate in the synthesis of viral RNA. As a result PSI-6130 reduces the efficacy of further elongation of HCV RNA by NS5B. [2]
Studies reported PSI-6130 HCV replication inhibition effects. PSI-6130 activity of HCV replication was determined in Huh7 cells with a subgenomic genotype 1b Con1 strain. And the mean IC50 was 0.6 μM. And another study showed that PSI-6130 inhibited HCV GT-1b (Con1 strain) and GT-1a (H77 strain) subgenomic RNA replication, with similar levels of potency, whose mean EC 50 values are 0.51 and 0.30 μM, respectively. [1, 2]
PSI-6130 could be transformed into two active metabolites, RO2433 and PSI-6026 respectively, in human primary hepatocytes by enzymes. Moreover, PSI-6130 showed little or no cytotoxicity  against different cells, including human peripheral blood mononuclear and human bone marrow progenitor cells. [1, 3]
Assessments of PSI-6130’s activity against other viruses in the Flaviviridae family were conducted, which illustrated that PSI-6130 was not active against viruses including BVDV, WNV, YFV, HBV, and HIV. The results also showed that PSI-6130 is a selective HCV inhibitor. [3]
References:
1.Ali S, Leveque V, Le Pogam S, et al. Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479. Antimicrobial agents and chemotherapy[J], 2008, 52(12): 4356-4369.
2.Ma H, Jiang W R, Robledo N, et al. Characterization of the metabolic activation of hepatitis C virus nucleoside inhibitor β-d-2′-deoxy-2′-fluoro-2′-C-methylcytidine (PSI-6130) and identification of a novel active 5′-triphosphate species[J]. Journal of Biological Chemistry, 2007, 282(41): 29812-29820.
3.Stuyver L J, McBrayer T R, Tharnish P M, et al. Inhibition of hepatitis C replicon RNA synthesis by beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine: a specific inhibitor of hepatitis C virus replication[J]. Antiviral chemistry & chemotherapy, 2006, 17(2): 79-87.

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References on PSI-6130

Selected replicon variants with low-level in vitro resistance to the hepatitis C virus NS5B polymerase inhibitor PSI-6130 lack cross-resistance with R1479.[Pubmed:18838588]

Antimicrob Agents Chemother. 2008 Dec;52(12):4356-69.

PSI-6130 (beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine) is a selective inhibitor of hepatitis C virus (HCV) replication that targets the NS5B polymerase. R7128, the prodrug of PSI-6130, has shown antiviral efficacy in patients chronically infected with HCV genotype 1a (GT-1a) and GT-1b. We observed that the compound exhibited potent in vitro activity against laboratory-optimized HCV replicons as well as against a panel of replicons containing NS5B HCV polymerases derived from GT-1a and GT-1b clinical isolates. We used the HCV replicon cell system to examine the emergence of variants with reduced sensitivity to PSI-6130. Short-term treatment of cells harboring the HCV subgenomic replicon with PSI-6130 cleared the replicon without generating resistant variants. Long-term culture of the cells under the compound selection generated the S282T substitution in a complex pattern with other amino acid substitutions in the NS5B polymerase. The presence of the coselected substitutions did not increase the moderate three- to sixfold loss of sensitivity to PSI-6130 mediated by the S282T substitution; however, their presence enhanced the replication capacity compared to the replication levels seen with the S282T substitution alone. We also observed a lack of cross-resistance between PSI-6130 and R1479 and demonstrated that long-term culture selection with PSI-6130 in replicon cells harboring preexisting mutations resistant to R1479 (S96T/N142T) results in the emergence of the S282T substitution and the reversion of S96T to wild-type serine. In conclusion, PSI-6130 presents a high barrier to resistance selection in vitro, selects for variants exhibiting only low-level resistance, and lacks cross-resistance with R1479, supporting the continued development of the prodrug R7128 as a therapeutic agent for the treatment of HCV infection.

An efficient and diastereoselective synthesis of PSI-6130: a clinically efficacious inhibitor of HCV NS5B polymerase.[Pubmed:19642660]

J Org Chem. 2009 Sep 4;74(17):6819-24.

R7128 is the prodrug of 2'-deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130), a potent and selective inhibitor of HCV NS5B polymerase. Currently, R7128 is in clinical trials for the treatment of HCV infection. To support clinical development efforts, we needed an efficient and scalable synthesis of PSI-6130. We describe an improved, diastereoselective synthetic route starting with protected d-glyceraldehyde. No chiral reagents or catalysts were used to produce the three new contiguous stereocenters. Introduction of fluorine at the C-2 tertiary carbon was accomplished in a highly regio- and stereoselective manner through nucleophilic substitution on a cyclic sulfate. Scale-limiting chromatographic purifications were eliminated through the use of crystalline intermediates.

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.[Pubmed:17698842]

J Biol Chem. 2007 Oct 12;282(41):29812-20.

beta-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) is a potent inhibitor of hepatitis C virus (HCV) replication in the subgenomic HCV replicon system, and its corresponding 5'-triphosphate is a potent inhibitor of the HCV RNA polymerase in vitro. In this study the formation of PSI-6130-triphosphate was characterized in primary human hepatocytes. PSI-6130 and its 5'-phosphorylated derivatives were identified, and the intracellular concentrations were determined. In addition, the deaminated derivative of PSI-6130, beta-d-2'-deoxy-2'-fluoro-2'-C-methyluridine (RO2433, PSI-6026) and its corresponding phosphorylated metabolites were identified in human hepatocytes after incubation with PSI-6130. The formation of the 5'-triphosphate (TP) of PSI-6130 (PSI-6130-TP) and RO2433 (RO2433-TP) increased with time and reached steady state levels at 48 h. The formation of both PSI-6130-TP and RO2433-TP demonstrated a linear relationship with the extracellular concentrations of PSI-6130 up to 100 mum, suggesting a high capacity of human hepatocytes to generate the two triphosphates. The mean half-lives of PSI-6130-TP and RO2433-TP were 4.7 and 38 h, respectively. RO2433-TP also inhibited RNA synthesis by the native HCV replicase isolated from HCV replicon cells and the recombinant HCV polymerase NS5B with potencies comparable with those of PSI-6130-TP. Incorporation of RO2433-5'-monophosphate (MP) into nascent RNA by NS5B led to chain termination similar to that of PSI-6130-MP. These results demonstrate that PSI-6130 is metabolized to two pharmacologically active species in primary human hepatocytes.

A general and enantioselective approach to pentoses: a rapid synthesis of PSI-6130, the nucleoside core of sofosbuvir.[Pubmed:24670208]

J Am Chem Soc. 2014 Apr 23;136(16):5900-3.

An efficient route towards biologically relevant pentose derivatives is described. The de novo synthetic strategy features an enantioselective alpha-oxidation reaction enabled by a chiral amine in conjunction with copper(II) catalysis. A subsequent Mukaiyama aldol coupling allows for the incorporation of a wide array of modular two-carbon fragments. Lactone intermediates accessed via this route provide a useful platform for elaboration, as demonstrated by the preparation of a variety of C-nucleosides and fluorinated pentoses. Finally, this work has facilitated expedient syntheses of pharmaceutically active compounds currently in clinical use.

Description

PSI-6130 is a potent and selective inhibitor of HCV NS5B polymerase, and inhibits HCV replication with a mean IC50 of 0.6 μM.

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