Efficacy ofPhosphonylmethoxyalkyl Derivatives ofAdenine in Experimental HerpesSimplex Virus andVaccinia Virus Infections InVivo

(PMEA), and9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP)wereevaluated fortheir invivoefficacies inseveral animal modelinfections, i.e., miceinfected intravenously withvaccinia virus andmiceinfected intracutaneously, intraperitoneally, orintracerebraily with herpes simplex virus type1(HSV-1) ortype 2(HSV-2) orthymidine kinase-deficient (TK-)HSV-1.(S)HPMPA inhibited thedevelopment oftail lesions caused byvaccinia virus ifitwasadministered intraperitoneally orsubcutaneously atadosage aslowas5mg/kg perday.Allthree compounds completely suppressed thedevelopment ofskinlesions andthemortality associated therewith inhairless orathymic nudemice inoculated intracutaneously withHSV-1orTK-HSV-1, ifthey wereadministered topically ataconcentration aslowas0.1%;when(S)-HPMPA wasapplied topically ataconcentration of.0.3%, itcompletely abrogated mortality resulting fromintracutaneous HSV-2infection. Mostdramatic weretheeffects shownbythe compounds inmiceinoculated intracerebraily withHSV-1,HSV-2,orTK- HSV-1,inwhichallthree compounds given intraperitoneally atadoseof50or100mg/kg perdayeffected asignfficant reduction inthe mortality rateofHSV-1-infected mice. Themortality ofmiceinfected intracerebraily withHSV-2orTKHSV-1wassignificantly reduced evenwhen(S)-HPMPA wasgiven atdoses aslowas10mg/kg perday.These datapoint tothegreat potential ofthephosphonylmethoxyalkylpurines forbothtopical andparenteral treatment ofHSV-1, HSV-2, andTK-HSV-1infections. (S) -9-(3-Hydroxy -2-phosphonylmethoxypropyl)adenine