-OXO-1,4,2-DIOXAPHOSPHORINAN-5-YL)METHYL]CYTOSINE, AN INTRACELLULAR PRODRUG FOR S)-1-(3-HYDROXY-2-PHOSPHONYLMETHOXYPROPYL)CYTOSINE WITH IMPROVED THERAPEUTIC INDEX IN-VIVO

2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine (cyclic [cHPMPC]) w as evaluated as a novel antiviral agent in comparison with S)-1-(3-hyd roxy-2-phosphonylmethoxypropyl)cytosine (HPMPC). Evaluation for in vit ro activity against herpes simplex virus type 2 in MA-104 and MRC-5 ce lls showed that both cHPMPC and HPMPC have comparable activities and c ytotoxicities. cHPMPC was found to be stable on incubation in human pl asma and human liver homogenates. Intracellular metabolism studies rev ealed that cHPMPC was converted inside of the cells to HPMPC and then to the monophosphate, the diphosphate, and the monophosphate choline m etabolites. In a mouse herpes simplex virus type 2 encephalitis model, both cHPMPC and HPMPC exhibited similar potencies in vivo. Nephrotoxi city, which is the dose-limiting toxicity of HPMPC, was assessed in a 14-day repeated-dose toxicity study in rats; cHPMPC has an improved sa fety margin of greater than or equal to 13-fold over that of HPMPC.