guanosine-monophosphate and phosphoramidic-acid

guanosine-monophosphate has been researched along with phosphoramidic-acid* in 2 studies

Other Studies

2 other study(ies) available for guanosine-monophosphate and phosphoramidic-acid

Article	Year
Dual pro-drugs of 2'-C-methyl guanosine monophosphate as potent and selective inhibitors of hepatitis C virus. Bioorganic & medicinal chemistry letters, 2011, Oct-01, Volume: 21, Issue:19 We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2'-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism. Topics: Amides; AMP Deaminase; Antiviral Agents; Cell Line, Tumor; Drug Design; Drug Evaluation, Preclinical; Guanosine Monophosphate; Hepacivirus; Hepatitis C; Humans; Hydrolysis; Inhibitory Concentration 50; Microbial Sensitivity Tests; Molecular Structure; Nucleosides; Phosphoric Acids; Phosphorylation; Prodrugs; Stereoisomerism; Structure-Activity Relationship; Virus Replication	2011
Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus. Bioorganic & medicinal chemistry letters, 2010, Aug-15, Volume: 20, Issue:16 We herein report a novel double pro-drug approach applied to the anti-HCV agent 2'-beta-C-methyl guanosine. A phosphoramidate ProTide motif and a 6-O-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Modification of the ester and amino acid moieties lead to a compound INX-08189 that exhibits 10nM potency in the HCV genotype 1b subgenomic replicon, thus being 500 times more potent than the parent nucleoside. The potency of the lead compound INX-08189 was shown to be consistent with intracellular 2'-C-methyl guanosine triphosphate levels in primary human hepatocytes. The separated diastereomers of INX-08189 were shown to have similar activity in the replicon assay and were also shown to be similar substrates for enzyme processing. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV infection. Topics: Amides; Antiviral Agents; Cells, Cultured; Drug Design; Guanosine; Guanosine Monophosphate; Hepacivirus; Humans; Phosphoric Acids; Prodrugs	2010

Article

Year

Dual pro-drugs of 2'-C-methyl guanosine monophosphate as potent and selective inhibitors of hepatitis C virus.

Bioorganic & medicinal chemistry letters, 2011, Oct-01, Volume: 21, Issue:19

We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2'-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism.

Topics: Amides; AMP Deaminase; Antiviral Agents; Cell Line, Tumor; Drug Design; Drug Evaluation, Preclinical; Guanosine Monophosphate; Hepacivirus; Hepatitis C; Humans; Hydrolysis; Inhibitory Concentration 50; Microbial Sensitivity Tests; Molecular Structure; Nucleosides; Phosphoric Acids; Phosphorylation; Prodrugs; Stereoisomerism; Structure-Activity Relationship; Virus Replication

2011

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

Bioorganic & medicinal chemistry letters, 2010, Aug-15, Volume: 20, Issue:16

We herein report a novel double pro-drug approach applied to the anti-HCV agent 2'-beta-C-methyl guanosine. A phosphoramidate ProTide motif and a 6-O-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Modification of the ester and amino acid moieties lead to a compound INX-08189 that exhibits 10nM potency in the HCV genotype 1b subgenomic replicon, thus being 500 times more potent than the parent nucleoside. The potency of the lead compound INX-08189 was shown to be consistent with intracellular 2'-C-methyl guanosine triphosphate levels in primary human hepatocytes. The separated diastereomers of INX-08189 were shown to have similar activity in the replicon assay and were also shown to be similar substrates for enzyme processing. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV infection.

Topics: Amides; Antiviral Agents; Cells, Cultured; Drug Design; Guanosine; Guanosine Monophosphate; Hepacivirus; Humans; Phosphoric Acids; Prodrugs

2010