Alkoxyalkyl
esters of
cidofovir (CDV) are orally active agents which inhibit the replication of a variety of
double stranded DNA (dsDNA) viruses including
variola,
vaccinia,
ectromelia, herpes simplex virus, cytomegalovirus, adenovirus and others. One of these compounds, hexadecyloxypropyl-CDV (HDP-CDV, CMX001) is in clinical development for prevention and treatment of
poxvirus infection, vaccination complications, and for
infections caused by cytomegalovirus, adenovirus, herpesviruses and other dsDNA viruses. This class of
lipid analogs is potentially prone to undergo omega oxidation of the alkyl moiety which can lead to a short chain
carboxylic acid lacking
antiviral activity. To address this issue, we synthesized a series of alkoxyalkyl or alkyl
glycerol esters of CDV and (
S)-HPMPA having modifications in the structure of the alkyl residue.
Antiviral activity was assessed in cells infected with
vaccinia,
cowpox or ectromelia viruses. Metabolic stability was determined in S9 membrane fractions from rat, guinea pig, monkey and human liver. All compounds had substantial
antiviral activity in cells infected with
vaccinia,
cowpox or
ectromelia. Metabolic stability was lowest in monkey liver S9 incubations where rapid disappearance of
HDP-CDV and HDP-(
S)-HPMPA was noted. Metabolic stability in monkey preparations increased substantially when a ω-1 methyl group (15-methyl-HDP-CDV) or a terminal cyclopropyl residue (14-cyclopropyl-tetradecyloxypropyl-CDV) was present in the alkyl chain. The most stable compound was 1-O-octadecyl-2-O-benzyl-sn-glycero-3-CDV (
ODBG-CDV) which was not metabolized extensively by monkey liver S9. In rat, guinea pig or human liver S9 incubations, most of the modified
antiviral compounds were considerably more stable.