Antiviral activity and pharmacokinetics of HOE 602, an acyclic nucleoside, in animal models

Role of Aldehyde Oxidase and Xanthine Oxidase in the Metabolism of Purine-Related Drugs

“…HOE 602 is a nucleobase analog of ganciclovir with high therapeutic efficacy against HSV and MCMV infections in mice (Winkler et al, 1990). Pharmacokinetic studies in mice and rhesus monkeys indicated that this prodrug is converted to ganciclovir via a three-step pathway (Fig.…”

“…Pharmacokinetic studies in mice and rhesus monkeys indicated that this prodrug is converted to ganciclovir via a three-step pathway (Fig. 11) and yields a 4 to 21-fold increase in exposure after oral administration in monkeys compared to an equivalent oral dose of ganciclovir (Winkler et al, 1990). The first step, oxidation of the 6-aminopurine moiety to guanine, is mediated by XO (Winkler et al, 1990).…”

“…11) and yields a 4 to 21-fold increase in exposure after oral administration in monkeys compared to an equivalent oral dose of ganciclovir (Winkler et al, 1990). The first step, oxidation of the 6-aminopurine moiety to guanine, is mediated by XO (Winkler et al, 1990). However, no further studies of HOE 602 have been published (Li et al, 2008).…”

“…However, no further studies of HOE 602 have been published (Li et al, 2008). (Winkler et al, 1990). XO: xanthine oxidase Valganciclovir, a valine ester of ganciclovir, is another example of prodrug approach to overcome the poor oral absorption of ganciclovir (Maag, 2002).…”

Synthesis, Oral Bioavailability and in vivo Activity of Acetal Derivatives of the Selective Antiherpesvirus Agent 9-(3-hydroxypropoxy) Guanine (BRL 44385)

“…However, like other acyclic analogues of guanosine it is only poorly absorbed after oral administration to animals ). 2-Aminopurine, 2,6-diaminopurine and 2-amino-6-alkoxypurine congeners of acyclovir, penciclovir and ganciclovir and some of their ester and ether derivatives have been reported (Krenitsky et al, 1984;Harnden et al, 1989;Vere Hodge et al, 1989;Winkler et al, 1990) to show improved absorption and to be converted to the antiviral agent in vivo, but acyclic acetal derivatives have not been evaluated previously for oral delivery of nucleoside analogues. In this publication, syntheses of novel acetal derivatives of BRL44385 and of its 2-aminopurine congener (BRL46720) are reported and their bioavailability and antiviral efficacy in mice are described.…”