Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus.
OBJECTIVE
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 (approximately 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.
McGuigan
Christopher
C
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3XF, UK. mcguigan@cardiff.ac.uk
Pathirana
Ranjith N
RN
Migliore
Marco
M
Adak
Rina
R
Luoni
Giovanna
G
Jones
Arwyn T
AT
Díez-Torrubia
Alberto
A
Camarasa
Maria-Jose
MJ
Velázquez
Sonsoles
S
Henson
Geoffrey
G
Verbeken
Erik
E
Sienaert
Rebecca
R
Naesens
Lieve
L
Snoeck
Robert
R
Andrei
Graciela
G
Balzarini
Jan
J
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004847:Epithelial Cells; D006367:HeLa Cells; D014645:Herpesvirus 3, Human / Q000187:drug effects*; D006801:Humans; D015603:Keratinocytes; D051379:Mice; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
D000998:Antiviral Agents; D001643:Bridged Bicyclo Compounds; C500967:Cf 1743; C526677:FV-100; D011355:Prodrugs; D011741:Pyrimidine Nucleosides