We reported previously that
purine 2-(hydroxymethyl)methylenecyclopropane analogs have good activity against
cytomegalovirus infection. A second-generation analog, (Z)-9-[[2,2-bis-(hydroxymethyl)cyclopropylidene]methyl]
guanine (ZSM-I-62,
cyclopropavir [CPV]), has particularly good activity against murine and human cytomegaloviruses (MCMV and HCMV) in vitro. To determine the oral activity of this compound in vivo, BALB/c or severe combined immunodeficient (SCID) mice infected with MCMV and two models using SCID mice implanted with human fetal tissue and subsequently infected with HCMV were used. In MCMV-infected normal mice, CPV
at 10 mg/kg of
body weight was highly effective in preventing mortality when administered at 24, 48, or 72 h post-viral inoculation and reduced titers of virus in tissues of SCID mice by 2 to 5 log10. In one HCMV model, human fetal
retinal tissue was implanted into the anterior chamber of the mouse eye and inoculated with the Toledo strain of HCMV, and in the second, human fetal thymus and liver tissues were implanted under the kidney
capsule of mice and then inoculated with HCMV. In general, replication of HCMV in both types of implant tissue increased from 7 through 21 to 28 days and then gradually decreased to undetectable levels by 8 weeks postinfection. Oral treatment with 45 or 15 mg of CPV/kg initiated 24 h after
infection was highly effective in reducing replication to undetectable levels in both models and was generally more effective than
ganciclovir. These data indicate that the
methylenecyclopropane analog, CPV, was highly efficacious in these four animal models and should be evaluated for use in HCMV
infections in humans.