Effective treatment of murine cytomegalovirus infections with methylenecyclopropane analogues of nucleosides

A number of new nucleoside analogues with a Z- or E-methylenecyclopropane s tructure exhibited significant activity against human and murine cytomegalo viruses (HCMV, MCMV) in tissue culture that was generally comparable to, or greater than, 9-[(1-3-dihydroxy-2-propoxy)methyl]guanine (ganciclovir, GCV ). Several of these analogues were chosen for further evaluation of therape utic efficacy utilizing a MCMV infection. Intraperitoneal (i.p) inoculation of 3-week-old Balb/c mice with 2.0 x 10(5) plaque forming units (pfu) of M CMV results in an acute, lethal infection with rapid virus replication in v isceral and glandular tissue, thus, making it an ideal model for identifyin g compounds that have potential for use in humans. Synadenol (QYL-284A) and synguanol (QYL-438) were administered i.p. once daily for 5 days initiated 6, 24, or 48 h post-viral infection. Significant protection was demonstrat ed at 50 and 16.7 mg/kg compared to placebo, with efficacy comparable to GC V. When delivered orally once or twice daily at 100 mg/kg per day, QYL-438 was active, but less effective than GCV. In addition, 2-amino-6-methoxypuri ne analogue (QYL-941) was active at 60 mg/kg administered orally twice dail y, comparable to GCV, while it's prodrug (QYL-972) was as effective as GCV at 40 mg/kg when delivered twice daily for 5 days. Additionally, analogue 2 -amino-6-cycIopropylaminopurine (QYL-769) was found to be highly efficaciou s when given orally twice daily for 5 days. Mortality of 0% and 13% was obs erved at 60 and 20 mg/kg, respectively, which was similar to GCV. Oral trea tment with QYL-769 or GCV reduced virus replication in target organs, but n either resulted in complete clearance of MCMV. These data indicate that the se new analogues have activity comparable to GCV when given orally to mice and should be evaluated further to assess their potential for use in humans . (C) 1999 Elsevier Science B.V. All rights reserved.