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

McGuigan, Christopher, Madela, Karolina, Aljarah, Mohamed, Gilles, Arnaud, Battina, S. K., Ramamurty, C. V. S., Rao, C. S., Vernachio, J., Hutchins, J., Hall, A., Kolykhalov, A., Henson, G. and Chamberlain, S. 2011. Dual pro-drugs of 2 '-C-methyl guanosine monophosphate as potent and selective inhibitors of hepatitis C virus. Biorganic and Medicinal Chemistry Letters 21 (19) , pp. 6007-6012. 10.1016/j.bmcl.2011.06.013

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: HCV; ProTide; Phosphoramidate; Nucleoside; Nucleotide; Polymerase; NS5B
Publisher: Elsevier
ISSN: 0960-894X
Last Modified: 03 Nov 2017 01:31
URI: http://orca.cf.ac.uk/id/eprint/9995

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