Potent anti-murine cytomegalovirus activity and reduced nephrotoxicity of ganciclovir cyclic phosphonate.
Ganciclovir cyclic phosphonate (SR3775) is a derivative of the R enantiomer (SR3773) of ganciclovir phosphonate (9-[((+/-)-1-hydroxymethyl-3-phosphono)propyloxymethyl]guanine), both of which are potent inhibitors of human ctyomegalovirus and murine cytomegalovirus (MCMV). Against wild-type and four drug-resistant strains of MCMV, SR3773 was 2.3- to 3-fold more potent than SR3775. SR3775 was about half as active as SR3773 against MCMV infections in severe combined immunodeficient mice. However, whereas SR3773 caused 20 to 30% destruction of renal tubules at 50 mg/kg of body weight per day (but exerted no toxicity at 25 mg/kg/day), SR3775 showed no deleterious renal effects at 600 mg/kg/day over 14 days. SR3775 has a therapeutic index at least 12 times higher than SR3773 in mice, making it a candidate for the treatment of human cytomegalovirus disease.
Smee
D F
DF
Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan 84322-5600, USA.
Reist
E J
EJ
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D002460:Cell Line; D003498:Cyclic P-Oxides / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D015774:Ganciclovir / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D006566:Herpesviridae Infections / Q000188:drug therapy* / Q000821:virology; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008826:Microbial Sensitivity Tests; D018146:Muromegalovirus / Q000187:drug effects*; D063065:Organophosphonates; D013237:Stereoisomerism; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D003498:Cyclic P-Oxides; D063065:Organophosphonates; C102791:ganciclovir cyclic phosphonate; C050216:9-(1-hydroxy-4-phosphinyl-2-butoxymethyl)guanine; D015774:Ganciclovir