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

Bioorg Med Chem Lett. 2011 Oct 1;21(19):6007-12. doi: 10.1016/j.bmcl.2011.06.013.

Christopher McGuigan ¹, Karolina Madela, Mohamed Aljarah, Arnaud Gilles, Srinivas K Battina, Changalvala V S Ramamurty, C Srinivas Rao, John Vernachio, Jeff Hutchins, Andrea Hall, Alexander Kolykhalov, Geoffrey Henson, Stanley Chamberlain

Affiliations

Affiliation

1 Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. mcguigan@cf.ac.uk

PMID: 21856153 DOI: 10.1016/j.bmcl.2011.06.013

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.

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