In vitro and in vivo activity of 1-O-hexadecylpropanediol-3-phospho-ganciclovir and 1-O-hexadecylpropanediol-3-phospho-penciclovir in cytomegalovirus and herpes simplex virus infections.
Human cytomegalovirus (HCMV) and herpes simplex virus (HSV) can cause a wide variety of clinical manifestations in man. Ganciclovir (GCV) is effective against HCMV infection when administered by the intravenous route and may be used orally in large doses for prophylaxis of HCMV infections in organ transplantation patients and in AIDS patients. In previous studies with acyclovir (ACV), we found that covalent attachment of an alkyl glycerol phosphate moiety greatly increased oral bioavailability and increased antiviral activity against hepatitis B virus. Adducts of ACV with alkyl propanediol phosphate were more active than the alkyl glycerol phosphate analogue in vitro in 2.2.15 cells, which constitutively produce hepatitis B virus. To see if this strategy would work for two other poorly absorbed nucleoside analogues, we synthesized 1-O-hexadecylpropanediol-3-phospho-GCV (HDP-P-GCV) and 1-O-hexadecyl-propanediol-3-phospho-penciclovir (HDP-P-PCV), and evaluated the in vitro antiviral activity, selectivity and oral antiviral activity of both compounds versus GCV or PCV in mice infected with HSV-1 or HDP-P-GCV versus murine cytomegalovirus (MCMV). HDP-P-GCV is orally active in both MCMV and HSV-1 infection in mice with antiviral activity equivalent to (HSV-1) or greater than oral GCV (MCMV). Oral HDP-P-PCV was more active than PCV orally versus intranasal HSV-1 infection in mice.
Hostetler
K Y
KY
Department of Medicine, University of California, San Diego, La Jolla 92093-0676, USA. khostetler@ucsd.edu
Rybak
R J
RJ
Beadle
J R
JR
Gardner
M F
MF
Aldern
K A
KA
Wright
K N
KN
Kern
E R
ER
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001682:Biological Availability; D001711:Biotransformation; D002460:Cell Line / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects* / Q000502:physiology; D003586:Cytomegalovirus Infections / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D015774:Ganciclovir / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006561:Herpes Simplex / Q000188:drug therapy*; D006801:Humans; D008168:Lung; D051379:Mice; D008807:Mice, Inbred BALB C; D018146:Muromegalovirus / Q000187:drug effects / Q000502:physiology; D018139:Simplexvirus / Q000187:drug effects* / Q000502:physiology; D010948:Viral Plaque Assay; D014779:Virus Replication / Q000187:drug effects
C407662:1-O-hexadecyl-propanediol-3-phospho-ganciclovir; C444359:1-O-hexadecylpropanediol-3-phospho-penciclovir; D000998:Antiviral Agents; D015774:Ganciclovir