Alkoxyalkyl esters of 9-(s)-(3-hydroxy-2-phosphonomethoxypropyl) adenine are potent and selective inhibitors of hepatitis B virus (HBV) replication in vitro and in HBV transgenic mice in vivoAntimicrob Agents Chemother (2009)
AbstractAlkoxyalkyl esters of acyclic nucleoside phosphonates have previously been shown to have increased antiviral activity when they are administered orally in animal models of viral diseases, including lethal infections with vaccinia virus, cowpox virus, ectromelia virus, murine cytomegalovirus, and adenovirus. 9-(S)-(3-Hydroxy-2-phosphonomethoxypropyl)adenine [(S)-HPMPA] was previously shown to have activity against hepatitis B virus (HBV) in vitro. To assess the effect of alkoxyalkyl esteriﬁcation of (S)-HPMPA, we prepared the hexadecyloxypropyl (HDP), 15-methyl-hexadecyloxypropyl (15M-HDP), and octadecyloxyethyl (ODE) esters and compared their activities with the activity of adefovir dipivoxil in vitro and in vivo. Alkoxyalkyl esters of (S)-HPMPA were 6 to 20 times more active than unmodiﬁed (S)-HPMPA on the basis of their 50% effective concentrations in 2.2.15 cells. The increased antiviral activity appeared to be due in part to the increased uptake and conversion of HDP-(S)-HPMPA to HPMPA diphosphate observed in HepG2 cells in vitro. HDP-(S)-HPMPA retained full activity against HBV mutants resistant to lamivudine (L180M, M204V), but cross-resistance to a mutant resistant to adefovir (N236T) was detected. HDP-(S)-HPMPA is orally bioavailable and provides excellent liver exposure to the drug. Oral treatment of HBV transgenic mice with HDP-(S)-HPMPA, 15M-HDP-(S)-HPMPA, and ODE-(S)-HPMPA for 14 days reduced liver HBV DNA levels by roughly 1.5 log units, a response equivalent to that of adefovir dipivoxil.
- Hepatitis B,
- transgenic mice
Publication DateJanuary 1, 2009
Citation InformationMorrey, J. D., B. E. Korba, J. R. Beadle, D. L. Wyles, and K. Y. Hostetler. 2009. Alkoxyalkyl esters of 9-(s)-(3-hydroxy-2-phosphonomethoxypropyl) adenine are potent and selective inhibitors of hepatitis B virus (HBV) replication in vitro and in HBV transgenic mice in vivo. Antimicrob Agents Chemother 53:2865-2870. PMID19398648 PMCPMC2704649