We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus.
- Authors
Christopher McGuigan; Ranjith N. Pathirana; Marco Migliore; Rina Adak; Giovanna Luoni; Arwyn T. Jones; Alberto DÃez-Torrubia; Maria-Jose Camarasa; Sonsoles Velázquez; Geoffrey Henson; Erik Verbeken; Rebecca Sienaert; Lieve Naesens; Robert Snoeck; Graciela Andrei; Jan Balzarini
- Abstract
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 (â¼14%). A Captisol® admixture and the 5â²-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 5â²-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.
- Subjects
NUCLEOSIDES; VARICELLA-zoster virus; HERPESVIRUS diseases; KERATINOCYTES
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2007, Vol 60, Issue 6, p1316
- ISSN
0305-7453
- Publication type
Article
- DOI
10.1093/jac/dkm376