Alkoxyalkyl
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.