Efficacy of oral active ether lipid analogs of cidofovir in a lethal mousepox model.

Abstract

Cidofovir (CDV) is a highly effective inhibitor of orthopoxvirus replication and may be used intravenously to treat smallpox or complications arising from the smallpox vaccine under an investigational new drug application (IND). However, CDV is absorbed poorly following oral administration and is inactive orally. To improve the bioavailability of CDV, others synthesized alkoxyalkanol esters of CDV and observed >100-fold more activity than unmodified CDV against cowpox, vaccinia, and variola virus (VARV) replication. These ether lipid analogs of CDV have high oral bioavailability in mice. In this study, we compared the oral activity of CDV with the hexadecyloxypropyl (HDP)-, octadecyloxyethyl-, oleyloxypropyl-, and oleyloxyethyl-esters of CDV in a lethal, aerosol ectromelia virus (ECTV) challenge model in A/NCR mice. Octadecyloxyethyl-CDV appeared to be the most potent CDV analog as a dose regimen of 5 mg/kg started 4 h following challenge completely blocked virus replication in spleen and liver, and protected 100% of A/NCR mice, although oral, unmodified CDV was inactive. These results suggest that this family of compounds deserves further evaluation as poxvirus antiviral.

• Authors: R Mark Buller, Gelita Owens, Jill Schriewer, Lora Melman, James R Beadle, Karl Y Hostetler
• Journal: Virology (Virology) Vol. 318 Issue 2 Pg. 474-81 (Jan 20 2004) ISSN: 0042-6822 [Print] United States
• PMID: 14972516 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antiviral Agents
• Esters
• Organophosphonates
• Organophosphorus Compounds
• Cytosine
• Cidofovir

Topics

• Administration, Oral
• Animals
• Antiviral Agents (chemistry, therapeutic use)
• Cidofovir
• Cytosine (analogs & derivatives, chemistry, therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Ectromelia virus (drug effects)
• Ectromelia, Infectious (drug therapy)
• Esters (chemistry, therapeutic use)
• Female
• Inhibitory Concentration 50
• Mice
• Molecular Structure
• Organophosphonates
• Organophosphorus Compounds (chemistry, therapeutic use)