In vivo Antiretroviral Efficacy of Oral bis(POM)-PMEA, the bis(Pivaloyloxymethyl)prodrug of 9-(2-Phosphonylmethoxyethyl) adenine (PMEA)

Abstract

The bis-pivaloyloxymethyl(POM)- and diphenyl-ester prodrugs of the broad spectrum antiviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) have been evaluated in vivo for antiviral efficacy upon oral administration in severe combined immune deficiency (SCID) mice infected with Moloney murine sarcoma virus (MSV). Oral bis (POM)-PMEA proved highly efficient in delaying MSV-induced tumor formation and associated death, its effect being equal to that of subcutaneous PMEA at an equimolar dose. Compared to bis(POM)-PMEA, oral diphenyl-PMEA had lower antiviral efficacy, whereas PMEA as such was poorly effective when administered orally. Our studies indicate that bis(POM)-PMEA must have a favorable oral bioavailability and justify its clinical investigation as an oral prodrug of PMEA in the treatment of HIV infections.