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

McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X, 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:	18 Oct 2022 12:28
URI:	https://orca.cardiff.ac.uk/id/eprint/9995

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