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Phosphoramidate ProTides of 2'-C-methylguanosine as highly potent inhibitors of hepatitis C virus. Study of their in vitro and in vivo properties.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2010 Jul 08; Vol. 53 (13), pp. 4949-57. - Publication Year :
- 2010
-
Abstract
- Hepatitis C virus infection constitutes a serious health problem in need of more effective therapies. Nucleoside analogues with improved exposure, efficacy, and selectivity are recognized as likely key components of future HCV therapy. 2'-C-Methylguanosine triphosphate has been known as a potent inhibitor of HCV RNA polymerase for some time, but the parent nucleoside is only moderately active due to poor intracellular phosphorylation. We herein report the application of phosphoramidate ProTide technology to bypass the rate-limiting initial phosphorylation of this nucleoside. Over 30 novel ProTides are reported, with variations in the aryl, ester, and amino acid regions. l-Alanine compounds are recognized as potent and selective inhibitors of HCV in replicon assay but lack rodent plasma stability despite considerable ester variation. Amino acid variation retaining the lead benzyl ester moiety gives an increase in rodent stability but at the cost of potency. Finally l-valine esters with ester variation lead to potent, stable compounds. Pharmacokinetic studies on these agents in the mouse reveal liver exposure to the bioactive triphosphate species following single oral dosing. Systemic exposure of the ProTide and parent nucleoside are low, indicating possible low toxicity in vivo, while liver concentrations of the active species may be predictive of efficacy in the clinic. This represents one of the most thorough cross-species studies of ProTides to date.
- Subjects :
- Adenosine Triphosphate analysis
Amides chemistry
Amides pharmacology
Animals
Antiviral Agents chemistry
Antiviral Agents pharmacology
Cell Line
Female
Guanosine chemical synthesis
Guanosine chemistry
Guanosine pharmacology
Hepatitis C virology
Humans
Liver metabolism
Liver virology
Magnetic Resonance Spectroscopy
Mice
Mice, Inbred ICR
Phosphoric Acids chemistry
Phosphoric Acids pharmacology
Amides chemical synthesis
Antiviral Agents chemical synthesis
Guanosine analogs & derivatives
Hepacivirus physiology
Hepatitis C drug therapy
Phosphoric Acids chemical synthesis
Virus Replication drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 53
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20527890
- Full Text :
- https://doi.org/10.1021/jm1003792