Three acyclic nucleoside phosphonates (ANPs) have been formally approved for clinical use in the treatment of 1) cytomegalovirus retinitis in AIDS patients (cidofovir, by the intravenous route), 2) chronic hepatitis B virus (HBV) infections (adefovir dipivoxil, by the oral route), and 3) human immunodeficiency virus (HIV) infections (tenofovir disoproxil fumarate, by the oral route). The activity spectrum of cidofovir {(S)- 1-[3-hydroxy-2-(phosphononiethoxy)propyl]cytosine {(S)-HPMPC)]1, like that of (S)-HPMPA {(S)-9-[3-hydroxy-2-(phosphononiethoxy)propyl]adenine} and (S)-HPMPDAP {(S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2,6-diaminopurinel, encompasses a broad spectrum of DNA viruses, including polyoma, papilloma-, adeno-, herpes-, and poxviruses. Adefovir {9-[2(phosphonomethoxy)ethyl]adenine (PMEA)l and tenofovir [(R)-9-[2-(phosphonomethoxy) propylladenine [(R)-PMPA)]1 are particularly active against retroviruses (i.e., HIV) and hepadnaviruses (i.e., HBV); additionally, PMEA also shows activity against herpes- and poxviruses. We have recently identified a new class of ANPs, namely 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines, named, in analogy with their alkylpurine counterparts, HPMPO-DAPy, PMEO-DAPy, and (R)PMPO-DAPy. These compounds exhibit an antiviral activity spectrum and potency that is similar to that of (S)-HPMPDAP, PMEA, and (R)-PMPA, respectively. Thus, PMEO-DAPy and (R)-PMPO-DAPy, akin to PMEA and (R)-PMPA, proved particularly active against HIV- 1, HIV-2, and the murine retrovirus Moloney sarcoma virus (MSV). PMEO-DAPy and (R)-PMPO-DAPy also showed potent activity against both wild-type and lamivudine- resistant strains of HBV. HPMPO-DAPy was found to inhibit different poxviruses (i e., vaccinia, cowpox, and orf) at a similar potency as cidofovir. HPMPO-DAPy also proved active against adenoviruses. In vivo, HPMPO-DAPy proved equipotent to cidofovir in suppressing vaccinia virus infection (tail lesion formation) in immunocompetent mice and promoting healing of disseminated vaccinia lesions in athymic-nude mice. The 6-[2-(phosphonomethoxy)alkoxyl]-2,4-diaminopyrimidines offer substantial Potential for the treatment of a broad range of retro, hepadna-, herpes-, adeno, and poxvirus infections.
