JAC Advance Access first published online on October 22, 2007
This version published online on November 7, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm376
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Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus
1 Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK 2 Instituto de Quimica Medica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain 3 FermaVir Pharmaceuticals, Inc., 420 Lexington Avenue, Suite 445, New York, NY 10170, USA 4 Morphology and Molecular Pathology, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium 5 Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Received 20 June 2007; returned 27 July 2007; revised 3 September 2007; accepted 4 September 2007
* Corresponding author. Tel/Fax: +44-029-2087-4537; E-mail: mcguigan{at}cardiff.ac.uk
Objectives: To progress the anti-varicella-zoster-virus (VZV) aryl bicyclic nucleoside analogues (BCNAs) to the point of Phase 1 clinical trial for herpes zoster.
Methods: A new chromatography-free synthetic access to the lead anti-VZV aryl BCNAs is reported. The anti-VZV activity of lead Cf1743 was evaluated in monolayer cell cultures and organotypic epithelial raft cultures of primary human keratinocytes. Oral dosing in rodents and preliminary pharmacokinetics assessment was made, followed by an exploration of alternative formulations and the preparation of pro-drugs. We also studied uptake into cells of both parent drug and pro-drug using fluorescent microscopy and biological assays.
Results: Cf1743 proved to be significantly more potent than all reference anti-VZV compounds as measured either by inhibition of infectious virus particles and/or by viral DNA load. However, the very low water solubility of this compound gave poor oral bioavailability (
14%). A Captisol® admixture and the 5'-monophosphate pro-drug of Cf1743 greatly boosted water solubility but did not significantly improve oral bioavailability. The most promising pro-drug to emerge was the HCl salt of the 5'-valyl ester, designated as FV-100. Its uptake into cells studied using fluorescent microscopy and biological assays indicated that the compound is taken up by the cells after a short period of incubation and limited exposure to drug in vivo may have beneficial effects.
Conclusions: On the basis of its favourable antiviral and pharmacokinetic properties, FV-100 is now being pursued as the clinical BCNA candidate for the treatment of VZV shingles.
Key Words: antiviral , VZV , BCNAs , herpes
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  C. McGuigan and J. Balzarini FV100 as a new approach for the possible treatment of varicella-zoster virus infection J. Antimicrob. Chemother., October 1, 2009; 64(4): 671 - 673. [Abstract] [Full Text] [PDF]
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