PSI-6206

PSI-6206 (as known as RO-2433 or GS-331007), β-_D-2’-deoxy-2’-fluoro-2’-C-methyluridine, is the deaminated derivative of PSI-6130, β-_D-2’-deoxy-2’-fluoro-2’-C-methylcytidine, which is a potent inhibitor of hepatitis C virus (HCV) replication in the subgenomic HCV reolicon system.  PSI-6206, itself, does not shown any inhibitory activity towards HCV replication in the HCV subgenomic replicon system. However, the its triphosphate form, RO2433-TP, is a potent inhibitor of RNA synthesis by HCV polymerase, which inhibits both the RNA sysnthesis activity of HCV replicase (IC₅₀ = 1.19 uM) and the RNA synthesis activity of the recombinant HCV Con1 NS58 on a heteropolymeric RNA template derived from the 3’-end of the negative strand of the HCV genome (IC₅₀ = 0.52 uM and K_i = 0.141 uM).

Reference

Han Ma, Wen-Rong Jiang, Nicole Robledo, Vincent Leveque, Samir Ali, Teresa Lara-Jamie, Mohammad Masjedizadeh, David B. Smith, Nick Cammack, Klaus Klumpp, and Julian Symons. Characterization of the metabolic ctivation 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. The Journal of Biological Chemistry 2007; 282(41): 29812-29820

Pharmacokinetics, safety, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor for hepatitis C virus, following single ascending doses in healthy subjects.[Pubmed:23262999]

Antimicrob Agents Chemother. 2013 Mar;57(3):1201-8.

To investigate the pharmacokinetics, safety, and tolerability of GS-9851 (formerly PSI-7851), a new nucleotide analog inhibitor of hepatitis C virus (HCV), we conducted a double-blind, parallel, placebo-controlled, randomized, single-ascending-dose study. Healthy subjects received oral doses of 25 to 800 mg GS-9851. Peak concentrations of GS-9851 in plasma were achieved more rapidly than those of the metabolites GS-566500 (formerly PSI-352707) and GS-331007 (formerly PSI-6206), with time to maximum concentration of drug in plasma (t(max)) values of 1.0 to 1.8 h, 1.5 to 3.0 h, and 3.0 to 6.0 h, respectively. The majority of systemic drug exposure was from the nucleoside GS-331007, with maximum concentration of drug in plasma (C(max)) and area under the concentration-time curve to the last measurable concentration (AUC(0-t)) values at least 7- and 41-fold higher, respectively, than those obtained for GS-9851 after adjusting for differences in molecular weight. The terminal elimination half-life (t(1/2)) of GS-331007 increased with the dose, achieving a t(1/2) of 25.7 h at 800 mg GS-9851. Dose proportionality was not observed for GS-331007. The majority of drug recovered in urine was in the form of GS-331007, with the percentage of this metabolite in urine samples ranging from 57% to 27% with increasing dose. GS-9851 was generally well tolerated, with no maximum tolerated dose identified. In conclusion, GS-9851 and its metabolites demonstrated a favorable pharmacokinetic profile consistent with once-daily dosing, and therefore, further clinical studies evaluating GS-9851 in HCV-infected patients are warranted.

Discovery of a beta-d-2'-deoxy-2'-alpha-fluoro-2'-beta-C-methyluridine nucleotide prodrug (PSI-7977) for the treatment of hepatitis C virus.[Pubmed:20845908]

J Med Chem. 2010 Oct 14;53(19):7202-18.

Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. beta-d-2'-Deoxy-2'-alpha-fluoro-2'-beta-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs of the 5'-phosphate derivative of the beta-d-2'-deoxy-2'-alpha-fluoro-2'-beta-C-methyluridine nucleoside were prepared and showed significant potency in the HCV subgenomic replicon assay (<1 muM) and produced high levels of triphosphate 6 in primary hepatocytes and in the livers of rats, dogs, and monkeys when administered in vivo. The single diastereomer 51 of diastereomeric mixture 14 was crystallized, and an X-ray structure was determined establishing the phosphoramidate stereochemistry as Sp, thus correlating for the first time the stereochemistry of a phosphoramidate prodrug with biological activity. 51 (PSI-7977) was selected as a clinical development candidate.

A liquid chromatography-tandem mass spectrometry method for the quantitative determination of diastereomers of a phosphoramidate nucleotide prodrug (PSI-7851) in human plasma.[Pubmed:21842514]

Biomed Chromatogr. 2012 May;26(5):583-8.

A rapid and stereospecific method using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) for the separation and determination of PSI-7851 diastereomers in human K(2)EDTA plasma has been developed. The analytical method involves direct protein precipitation with acetonitrile, followed by separation of the diastereomers on a Luna C(1)(8) column, positive mode electrospray ionization and selected reaction monitoring mode mass spectrometry detection. The mobile phase composition and pH were investigated for the resolution of the two diastereomers of PSI-7851. The optimized method showed good resolution (R(s) = 4.8) within short analysis time (approximately 8 min). The assay range was 5-2500 ng/mL for both diastereomers using a 1/x(2) weighted linear regression analysis for standard curve fitting. Replicate sample analysis indicated that intra- and inter-day accuracy and precision were within +/-15.0%. The recovery of diastereomers from human plasma was greater than 85% and no significant matrix effect was observed. The method was demonstrated to be sensitive, selective and robust, and was successfully used to support clinical studies.

Towards interference free HPLC-SERS for the trace analysis of drug metabolites in biological fluids.[Pubmed:28063334]

J Pharm Biomed Anal. 2017 Mar 20;136:38-43.

Sofosbuvir metabolite, 2'-deoxy-2'-fluoro-2'-C-methyluridine (PSI-6206) was studied for the first time by surface enhanced Raman spectroscopy (SERS) using the paper-based SERS substrate. The quantification limit of PSI-6206 by SERS was found to be 13ngL(-1) (R(2) value=0.959, RSD=5.23%). For the structural and quantitative analysis of PSI-6206 in blood plasma, an interference-free HPLC-SERS method was developed and compared to HPLC-DAD and HPLC-MS methods. The SERS quantification of the drug by the paper substrate was 4 orders of magnitude more sensitive than that by the diode array detector. In addition, the SERS detection provided unique structural identification of the drug in blood plasma, similar to Mass spectroscopy detector. Due to the disposable nature of the SERS substrate, the new method does not suffer from the known "memory effect" which is known to lead to false positive identification in traditional HPLC-SERS methods. Therefore, the presented HPLC-paper SERS platform holds great potential for the sensitive and cost effective determination of drugs and their metabolites in biological fluids.

Pharmacokinetics, pharmacodynamics, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor, following multiple ascending doses in patients with chronic hepatitis C infection.[Pubmed:23263000]

Antimicrob Agents Chemother. 2013 Mar;57(3):1209-17.

We conducted this double-blind, parallel-group, placebo-controlled, randomized, multiple-ascending-dose study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-9851 (formerly PSI-7851) in treatment-naive patients infected with hepatitis C virus (HCV) genotype 1. Thirty-two patients received active doses up to 400 mg of GS-9851 once daily for 3 days. GS-9851 and the metabolite GS-566500 (formerly PSI-352707) were rapidly cleared from the plasma, with half-life (t(1/2)) values of approximately 1 h for GS-9851 and 3 h for GS-566500. Accumulation (21%) was observed only for GS-331007 (formerly PSI-6206) after multiple dosing. GS-331007 was the primary drug-related moiety in the plasma and urine. Increases in the GS-9851, GS-566500, and GS-331007 maximum concentrations in plasma (C(max)) and area under the concentration-time curve (AUC) were less than dose proportional, particularly at the highest doses. The decline in plasma HCV RNA levels was dose dependent, and a mean maximal change from the baseline of -1.95 log(10) IU/ml was obtained for 400 mg GS-9851, compared with -0.090 log(10) IU/ml for the placebo. Most patients had a decrease in HCV RNA of >/=1.0 log(10) IU/ml after 3 days' dosing with 400 mg GS-9851. No virologic resistance was observed. GS-9851 was generally well tolerated, with no notable differences in adverse event frequency across doses. The pharmacokinetic profile observed in this study was similar to that seen in a single-ascending-dose study in healthy subjects.

PSI-6206 (RO 2433) is the deaminated derivative of PSI-6130, which is a potent and selective inhibitor of HCV NS5B polymerase. PSI-6206 low potently inhibits HCV replicon with EC90 of >100 μM.

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