PSI-6130 | CAS#817204-33-4 | HCV NS5B polymerase inhibitor

MedKoo Cat#: 526778 | Name: PSI-6130

Description:

WARNING: This product is for research use only, not for human or veterinary use.

PSI-6130, also known as R 1656, is a potent and selective inhibitor of HCV NS5B polymerase. 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.

Chemical Structure

PSI-6130

CAS#817204-33-4

Theoretical Analysis

MedKoo Cat#: 526778

Name: PSI-6130

CAS#: 817204-33-4

Chemical Formula: C10H14FN3O4

Exact Mass: 259.0968

Molecular Weight: 259.24

Elemental Analysis: C, 46.33; H, 5.44; F, 7.33; N, 16.21; O, 24.69

Price and Availability

Size	Price	Availability
25mg	USD 450.00	2 Weeks
50mg	USD 750.00	2 Weeks
100mg	USD 1,650.00	2 Weeks

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Synonym

PSI-6130; PSI-6130; PSI-6130; R 1656; R-1656; R1656.

IUPAC/Chemical Name

4-amino-1-((2R,3S,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidin-2(1H)-one

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

SMILES Code

OC[C@@H]1[C@H]([C@](C)(F)[C@H](N2C(N=C(C=C2)N)=O)O1)O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Inhibitor of HCV NS5B polymerase.

In vitro activity:

The protected 2'-C-methylcytidine was obtained as a byproduct from the DAST fluorination and allowed for the preparation of two biologically active compounds from a common precursor. Compound 1 and 2'-C-methylcytidine were assayed in a subgenomic HCV replicon assay system and found to be potent and selective inhibitors of HCV replication. Compound 1 shows increased inhibitory activity in the HCV replicon assay compared to 2'-C-methylcytidine and low cellular toxicity. Reference: Clark JL, Hollecker L, Mason JC, Stuyver LJ, Tharnish PM, Lostia S, McBrayer TR, Schinazi RF, Watanabe KA, Otto MJ, Furman PA, Stec WJ, Patterson SE, Pankiewicz KW. Design, synthesis, and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem. 2005 Aug 25;48(17):5504-8. doi: 10.1021/jm0502788. PMID: 16107149.

In vivo activity:

Pharmacokinetic studies with rhesus monkeys indicated slow and incomplete absorption with a mean absorption time (MAT) of 4.6 h and an oral bioavailability of 24.0% +/- 14.3% (mean +/- standard deviation), with comparable mean apparent half-lives following i.v. (4.54 +/- 3.98 h) and oral (5.64 +/- 1.13 h) administrations. The average percentages of the total dose recovered unchanged and in deaminated form in the urine were 32.9% +/- 12.6% and 18.9% +/- 6.6% (i.v.) and 6.0% +/- 3.9% and 3.9% +/- 1.0% (oral), respectively. The total bioavailability, taking into account the parent drug and its deaminated metabolite 2'-deoxy-2'-fluoro-2'-C-methyluridine (PSI-6206), was 64% +/- 26%. PSI-6130 was present in the cerebrospinal fluid after oral and i.v. dosing. However, no deamination of radiolabeled PSI-6130 was detected after 8 h of incubation in monkey and human whole blood. An N(4)-modified prodrug of PSI-6130 (PSI-6419) was orally administered to monkeys, but it failed to improve the oral bioavailability of PSI-6130. Further studies are warranted to improve the oral bioavailability and reduce the deamination of PSI-6130 in order to explore the potential of this drug for the treatment of HCV-infected individuals. Reference: Asif G, Hurwitz SJ, Shi J, Hernandez-Santiago BI, Schinazi RF. Pharmacokinetics of the antiviral agent beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine in rhesus monkeys. Antimicrob Agents Chemother. 2007 Aug;51(8):2877-82. doi: 10.1128/AAC.00193-07. Epub 2007 Jun 11. PMID: 17562805; PMCID: PMC1932527.

	Solvent	mg/mL	mM
Solubility
	DMSO	50.0	192.87

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 259.24 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

Clark JL, Hollecker L, Mason JC, Stuyver LJ, Tharnish PM, Lostia S, McBrayer TR, Schinazi RF, Watanabe KA, Otto MJ, Furman PA, Stec WJ, Patterson SE, Pankiewicz KW. Design, synthesis, and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem. 2005 Aug 25;48(17):5504-8. doi: 10.1021/jm0502788. PMID: 16107149.

In vitro protocol:

In vivo protocol:

Asif G, Hurwitz SJ, Shi J, Hernandez-Santiago BI, Schinazi RF. Pharmacokinetics of the antiviral agent beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine in rhesus monkeys. Antimicrob Agents Chemother. 2007 Aug;51(8):2877-82. doi: 10.1128/AAC.00193-07. Epub 2007 Jun 11. PMID: 17562805; PMCID: PMC1932527.

1: Adhikary A, Kumar A, Rayala R, Hindi RM, Adhikary A, Wnuk SF, Sevilla MD. One-electron oxidation of gemcitabine and analogs: mechanism of formation of C3' and C2' sugar radicals. J Am Chem Soc. 2014 Nov 5;136(44):15646-53. doi: 10.1021/ja5083156. Epub 2014 Oct 23. PMID: 25296262; PMCID: PMC4227712. 2: Peifer M, Berger R, Shurtleff VW, Conrad JC, MacMillan DW. A general and enantioselective approach to pentoses: a rapid synthesis of PSI-6130, the nucleoside core of sofosbuvir. J Am Chem Soc. 2014 Apr 23;136(16):5900-3. doi: 10.1021/ja502205q. Epub 2014 Apr 9. PMID: 24670208; PMCID: PMC4210058. 3: Tong X, Le Pogam S, Li L, Haines K, Piso K, Baronas V, Yan JM, So SS, Klumpp K, Nájera I. In vivo emergence of a novel mutant L159F/L320F in the NS5B polymerase confers low-level resistance to the HCV polymerase inhibitors mericitabine and sofosbuvir. J Infect Dis. 2014 Mar 1;209(5):668-75. doi: 10.1093/infdis/jit562. Epub 2013 Oct 23. PMID: 24154738. 4: Costantini VP, Whitaker T, Barclay L, Lee D, McBrayer TR, Schinazi RF, Vinjé J. Antiviral activity of nucleoside analogues against norovirus. Antivir Ther. 2012;17(6):981-91. doi: 10.3851/IMP2229. Epub 2012 Aug 14. PMID: 22910194; PMCID: PMC7751060. 5: Pawlotsky JM, Najera I, Jacobson I. Resistance to mericitabine, a nucleoside analogue inhibitor of HCV RNA-dependent RNA polymerase. Antivir Ther. 2012;17(3):411-23. doi: 10.3851/IMP2088. Epub 2012 Mar 8. PMID: 22402762. 6: Lam AM, Espiritu C, Bansal S, Micolochick Steuer HM, Zennou V, Otto MJ, Furman PA. Hepatitis C virus nucleotide inhibitors PSI-352938 and PSI-353661 exhibit a novel mechanism of resistance requiring multiple mutations within replicon RNA. J Virol. 2011 Dec;85(23):12334-42. doi: 10.1128/JVI.05639-11. Epub 2011 Sep 28. PMID: 21957306; PMCID: PMC3209386. 7: Le Pogam S, Seshaadri A, Ewing A, Kang H, Kosaka A, Yan JM, Berrey M, Symonds B, De La Rosa A, Cammack N, Nájera I. RG7128 alone or in combination with pegylated interferon-α2a and ribavirin prevents hepatitis C virus (HCV) Replication and selection of resistant variants in HCV-infected patients. J Infect Dis. 2010 Nov 15;202(10):1510-9. doi: 10.1086/656774. Epub 2010 Oct 13. PMID: 20942646. 8: Seden K, Back D, Khoo S. New directly acting antivirals for hepatitis C: potential for interaction with antiretrovirals. J Antimicrob Chemother. 2010 Jun;65(6):1079-85. doi: 10.1093/jac/dkq086. Epub 2010 Mar 23. PMID: 20335191. 9: Wang P, Chun BK, Rachakonda S, Du J, Khan N, Shi J, Stec W, Cleary D, Ross BS, Sofia MJ. An efficient and diastereoselective synthesis of PSI-6130: a clinically efficacious inhibitor of HCV NS5B polymerase. J Org Chem. 2009 Sep 4;74(17):6819-24. doi: 10.1021/jo901345j. PMID: 19642660. 10: Ali S, Leveque V, Le Pogam S, Ma H, Philipp F, Inocencio N, Smith M, Alker A, Kang H, Najera I, Klumpp K, Symons J, Cammack N, Jiang WR. 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. doi: 10.1128/AAC.00444-08. Epub 2008 Oct 6. PMID: 18838588; PMCID: PMC2592884. 11: De Clercq E. Emerging antiviral drugs. Expert Opin Emerg Drugs. 2008 Sep;13(3):393-416. doi: 10.1517/14728214.13.3.393. PMID: 18764719. 12: Bassit L, Grier J, Bennett M, Schinazi RF. Combinations of 2'-C-methylcytidine analogues with interferon-alpha2b and triple combination with ribavirin in the hepatitis C virus replicon system. Antivir Chem Chemother. 2008;19(1):25-31. doi: 10.1177/095632020801900104. PMID: 18610555; PMCID: PMC2742417. 13: McCown MF, Rajyaguru S, Le Pogam S, Ali S, Jiang WR, Kang H, Symons J, Cammack N, Najera I. The hepatitis C virus replicon presents a higher barrier to resistance to nucleoside analogs than to nonnucleoside polymerase or protease inhibitors. Antimicrob Agents Chemother. 2008 May;52(5):1604-12. doi: 10.1128/AAC.01317-07. Epub 2008 Feb 19. PMID: 18285474; PMCID: PMC2346640. 14: Murakami E, Niu C, Bao H, Micolochick Steuer HM, Whitaker T, Nachman T, Sofia MA, Wang P, Otto MJ, Furman PA. The mechanism of action of beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine involves a second metabolic pathway leading to beta-D-2'-deoxy-2'-fluoro-2'-C-methyluridine 5'-triphosphate, a potent inhibitor of the hepatitis C virus RNA-dependent RNA polymerase. Antimicrob Agents Chemother. 2008 Feb;52(2):458-64. doi: 10.1128/AAC.01184-07. Epub 2007 Nov 12. PMID: 17999967; PMCID: PMC2224766. 15: Ma H, Jiang WR, Robledo N, Leveque V, Ali S, Lara-Jaime T, Masjedizadeh M, Smith DB, Cammack N, Klumpp K, Symons J. 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. doi: 10.1074/jbc.M705274200. Epub 2007 Aug 13. PMID: 17698842. 16: Asif G, Hurwitz SJ, Shi J, Hernandez-Santiago BI, Schinazi RF. Pharmacokinetics of the antiviral agent beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine in rhesus monkeys. Antimicrob Agents Chemother. 2007 Aug;51(8):2877-82. doi: 10.1128/AAC.00193-07. Epub 2007 Jun 11. PMID: 17562805; PMCID: PMC1932527. 17: Murakami E, Bao H, Ramesh M, McBrayer TR, Whitaker T, Micolochick Steuer HM, Schinazi RF, Stuyver LJ, Obikhod A, Otto MJ, Furman PA. Mechanism of activation of beta-D-2'-deoxy-2'-fluoro-2'-c-methylcytidine and inhibition of hepatitis C virus NS5B RNA polymerase. Antimicrob Agents Chemother. 2007 Feb;51(2):503-9. doi: 10.1128/AAC.00400-06. Epub 2006 Nov 13. PMID: 17101674; PMCID: PMC1797721. 18: Stuyver LJ, McBrayer TR, Tharnish PM, Clark J, Hollecker L, Lostia S, Nachman T, Grier J, Bennett MA, Xie MY, Schinazi RF, Morrey JD, Julander JL, Furman PA, Otto MJ. 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. Antivir Chem Chemother. 2006;17(2):79-87. doi: 10.1177/095632020601700203. PMID: 17042329. 19: Clark JL, Hollecker L, Mason JC, Stuyver LJ, Tharnish PM, Lostia S, McBrayer TR, Schinazi RF, Watanabe KA, Otto MJ, Furman PA, Stec WJ, Patterson SE, Pankiewicz KW. Design, synthesis, and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methylcytidine, a potent inhibitor of hepatitis C virus replication. J Med Chem. 2005 Aug 25;48(17):5504-8. doi: 10.1021/jm0502788. PMID: 16107149.