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Sub micromolar inhibitors of HCV generated from inactive nucleosides by application of ProTide technology [Abstract]

McGuigan, Christopher, Perrone, P., Luoni, G., Kelleher, M. R., Daverio, F., Angell, A., Mulready, S., Congiatu, C., Rajyaguru, S., Martin, J., Leveque, V., Le Pogam, S., Najera, I., Klumpp, K. and Smith, D. 2007. Sub micromolar inhibitors of HCV generated from inactive nucleosides by application of ProTide technology [Abstract]. Antiviral Research 74 (3) , A36-A37. 10.1016/j.antiviral.2007.01.032

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Abstract

We report the application of our phosphoramidate ProTide technology to various 4′-substituted ribonucleoside analogues, designed as potential inhibitors of hepatitis C virus (HCV) (Fig. 1). Thus, ProTides were prepared from 4′-azidouridine (AZU), -cytidine (AZC), -adenosine (AZA) and -5-methyluridine (AZMeU), besides other 4′-substituted uridines and cytidines. In each case, ProTide families included variations in the aryl, ester, and amino acid regions. A number of compounds showed potent inhibitory properties in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. Of particular note was the sub-μM potency displayed by certain ProTides of AZU; a nucleoside analogue, which was itself inactive in the assay. In some cases, we were able to separate, and separately evaluate the phosphate stereoisomers generated in the synthesis; in a few cases the absolute phosphate stereochemistry was solved (Fig. 2). The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Additional Information: Abstract no. 24
Publisher: Elsevier
ISSN: 0166-3542
Last Modified: 18 Oct 2017 13:14
URI: http://orca.cf.ac.uk/id/eprint/6644

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