Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus

McGuigan, Christopher; Madela, Karolina; Aljarah, Mohamed; Gilles, Arnaud; Brancale, Andrea; Zonta, Nicola; Chamberlain, Stanley D.; Vernachio, John; Hutchins, Jeff; Hall, Andrea; Ames, Brenda; Gorovits, Elena L.; Ganguly, Babita; Kolykhalov, Alexander A.; Wang, Jin; Muhammad, Jerry; Patti, Joseph M.; Henson, Geoffrey

doi:10.1016/j.bmcl.2010.06.094

Cited by 94 publications

(101 citation statements)

References 12 publications

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“…The kinetics of INX-08189 antiviral activity were observed to be rapid, with an EC 50 of 35 nM after only 24 h of exposure with genotype 1b replicon-containing cells. Coupled with the rapid production of 2Ј-C-methyl GTP observed previously with INX-08189 in human hepatocytes (26), it is clear that cell entry and the metabolic conversion of INX-08189 is enhanced compared to that of the parent nucleoside, 2Ј-C-MeG. To determine the concentration of intracellular triphosphate required to achieve viral inhibition, 2Ј-C-MeGTP was quantified in genotype 1b replicon-expressing Huh-7 cells by LC-MS/MS analysis.…”

Section: Discussionsupporting

confidence: 52%

“…To further improve the performance of these compounds, alterations at the C-2 and C-6 positions of the base were investigated. It was found that phosphoramidate derivates of 6-O-methyl-2Ј-Cmethyl guanosine demonstrated improvements in cell-based potency, enhanced lipophilicity, cell permeability, and rapid intracellular conversion to the active triphosphate in human hepatocyte cultures (26). As a result of these studies, one compound that embodied all of these improvements, INX-08189, was selected for further characterization.…”

Section: Discussionmentioning

confidence: 99%

“…Given these measurements and assuming a hepatocellularity of 1 ϫ 10 8 cells in 1 g of liver (37), we calculated that 84 and 243 pmol of 2Ј-C-MeGTP per g of liver tissue would provide 50 and 90% levels of viral inhibition, respectively. These values were used to interpret the pharma- (26). The long intracellular half-life of the active triphosphate suggests that 2Ј-C-MeGTP concentrations in liver sufficient for antiviral activity are achievable with once-a-day dosing of INX-08189.…”

Section: Discussionmentioning

confidence: 99%

“…1) (26). This compound was selected from a number of phosphoramidate candidates because of its significant potency in replicon assays and its ability to efficiently generate intracellular triphosphate in primary human hepatocytes (26).…”

mentioning

confidence: 99%

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INX-08189, a Phosphoramidate Prodrug of 6- O -Methyl-2′- C -Methyl Guanosine, Is a Potent Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic and Pharmacodynamic Properties

Vernachio

Bleiman

Bryant

et al. 2011

Antimicrob Agents Chemother

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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INX-08189, a Phosphoramidate Prodrug of 6- O -Methyl-2′- C -Methyl Guanosine, Is a Potent Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic and Pharmacodynamic Properties

Vernachio

Bleiman

Bryant

et al. 2011

Antimicrob Agents Chemother

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“…The administration of a novel prodrug of the monophosphate of 2Ј-C-methylcytidine offers the possibility of obviating the side effect profile and increasing the antiviral efficacy compared to NM283. Prodrugs of the monophosphates of other nucleoside analogs have shown improved potency in vitro in HCV replicon or viral replication assays compared to the parent nucleoside analog (12,(17)(18)(19)26), and several are under clinical investigation.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′- C -Methylcytidine to Hepatitis C Virus-Infected Chimpanzees

Carroll

Koeplinger

Vavrek

et al. 2011

Antimicrob Agents Chemother

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. One approach to increase the antiviral efficacy of 2-C-methylcytidine is to increase the concentration of the active inhibitory species, the 5-triphosphate, in infected hepatocytes. HepDirect prodrug technology can increase intracellular concentrations of a nucleoside triphosphate in hepatocytes by introducing the nucleoside monophosphate into the cell, bypassing the initial kinase step that is often rate limiting. Screening for 2-C-methylcytidine triphosphate levels in rat liver after oral dosing identified 1-[3,5-difluorophenyl]-1,3-propandiol as an efficient prodrug modification. To determine antiviral efficacy in vivo, the prodrug was administered separately via oral and intravenous dosing to two HCV-infected chimpanzees. Circulating viral loads declined by ϳ1.4 log 10 IU/ml and by >3.6 log 10 IU/ml after oral and intravenous dosing, respectively. The viral loads rebounded after the end of dosing to predose levels. The results indicate that a robust antiviral response can be achieved upon administration of the prodrug.Chronic hepatitis C virus (HCV) infection is associated with increased incidence of liver fibrosis, cirrhosis, and hepatocellular carcinoma and is the leading cause of liver transplantation in the United States (13). The current standard for treatment is a combination of pegylated interferon alpha and ribavirin, which results in sustained viral response (SVR) (undetectable virus 6 months after the end of treatment) in 50% or 80% of treated patients harboring a genotype 1 or a genotype 2 or 3 infection, respectively (25). Thus, novel therapies resulting in higher SVR rates, particularly in the treatment of genotype 1 infections, are needed.Nucleoside analogs inhibiting the HCV RNA polymerase have been investigated as potential therapeutics to treat HCV infections. 2Ј-C-Methylcytidine inhibits HCV RNA replication in the replicon assay (consensus 1 50% effective concentration [EC 50 ], ϳ1 M) via inhibition of the HCV RNA polymerase, which is inhibited by the 2Ј-C-methylcytidine triphosphate in vitro in cell-free biochemical assays (50% inhibitory concentration [IC 50 ], ϳ0.2 M) (15). NM283, the 3Ј-O-valinyl ester prodrug of 2Ј-C-methylcytidine, has improved oral bioavailability compared to 2Ј-C-methylcytidine (21) and has been investigated in HCV-infected patients in clinical studies. In a phase IIb study, patients receiving NM283 in combination with pegylated interferon alpha and ribavirin at 24 weeks of therapy experienced mean viral load reductions of up to 3.3 log 10 IU/ml compared to 2.3 log 10 IU/ml reductions for patients receiving pegylated interferon-ribavirin alone (2). Due to the high incidence of gastrointestinal side effects, which required reduction of the highest daily dose of 800 mg to 200 or 400 mg, further development of NM283 was placed on hold.The HepDirect prodrug modifications of nucleoside 5Ј-monophosphates (NMP) are substituted cyclic 1,3-propanyl esters that offer an opportunity to bypass the initial phosphorylation step that is often rate limiting for the formation of...

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Synthesis of Phosphoramidate Prodrugs: ProTide Approach

Serpi

Madela

Pertusati

et al. 2013

CP Nucleic Acid Chemistry

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The ProTide (pronucleotide) approach is a prodrug strategy elaborated to deliver nucleoside monophosphate into the cell, circumventing the first and inefficient rate-limiting phosphorylation step of nucleosides and improving the cellular penetration of nucleotides. The ProTide of a nucleoside phosphate is a phosphoramidate prodrug consisting of an amino acid ester promoiety linked via P-N bond to a nucleoside aryl phosphate. Such prodrugs have increased lipophilicity and thus are capable of altering cell and tissue distribution. The ProTide technology was successfully and extensively applied to a wide variety of nucleoside phosphates, endowed with antiviral and anticancer activity. This unit describes two different synthetic strategies allowing the preparation of phosphoramidates of 6-O-methyl-2'-β-C-methylguanosine as model compounds for nucleosides having only the 5'-OH as reactive hydroxyl group, and phosphoramidates of 2'-β-D-arabinouridine (AraU) as model compounds for nucleosides containing two or more reactive hydroxyl groups.

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Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus

Cited by 94 publications

References 12 publications

INX-08189, a Phosphoramidate Prodrug of 6- O -Methyl-2′- C -Methyl Guanosine, Is a Potent Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic and Pharmacodynamic Properties

INX-08189, a Phosphoramidate Prodrug of 6- O -Methyl-2′- C -Methyl Guanosine, Is a Potent Inhibitor of Hepatitis C Virus Replication with Excellent Pharmacokinetic and Pharmacodynamic Properties

Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′- C -Methylcytidine to Hepatitis C Virus-Infected Chimpanzees

Synthesis of Phosphoramidate Prodrugs: ProTide Approach

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