brivudine and adefovir

New Adefovir (PMEA) prodrugs with a pro-moiety consisting of decyl or decyloxyethyl chain bearing hydroxyl function(s), hexaethyleneglycol or a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl unit were prepared starting from the tetrabutylammonium salt of the phosphonate drug and an appropriate alkyl bromide or tosylate. Analogously, two esters of Cidofovir [(S)-HPMPC] bearing a hexaethyleneglycol moiety were prepared. The activity of the prodrugs was evaluated in vitro against different virus families. A loss in the antiviral activities of the hydroxylated decyl or decyloxyethyl esters and hexaethyleneglycol esters of PMEA against human immunodeficiency virus (HIV) and herpesviruses [including herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (CMV)] occurred in comparison with the parent compound. On the other hand, the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of PMEA showed significant activities against HIV and herpesviruses. (S)-HPMPC prodrugs exhibited anti-cytomegalovirus activities in the same range as the parent drug, whereas the anti-HSV and anti-VZV activities were one- to seven-fold lower than that of Cidofovir.

Topics: Adenine; Animals; Antiviral Agents; Cell Line, Tumor; Cidofovir; Cytomegalovirus; Cytosine; Herpesvirus 3, Human; HIV; Humans; Organophosphonates; Prodrugs; Simplexvirus

Varicella-zoster virus (VZV) mutants were isolated under the pressure of different classes of antiviral compounds: (i) drugs that depend on the viral thymidine kinase (TK) for their activation, i.e. acyclovir (ACV), brivudin (BVDU), penciclovir (PCV) and sorivudine (BVaraU); (ii) drugs that are independent of the viral TK for their activation, i.e. 2-phosphonylmethoxyethyl (PME) derivatives of adenine (PMEA, adefovir) and 2,6-diaminopurine (PMEDAP); and (iii) drugs that do not require any metabolism to inhibit the viral DNA polymerase, i.e. foscarnet (PFA). Drug-resistant virus strains were obtained by serial passage of the OKA strain in human embryonic lung (HEL) fibroblasts and the different drug-resistant mutants were subsequently evaluated for their in vitro susceptibility to a broad range of antiviral drugs. Virus strains emerging under the pressure of ACV, BVDU and BVaraU were cross-resistant to all drugs that depend on the viral TK for activation, but remained susceptible to the acyclic nucleoside phosphonates (i.e. PMEA, PMEDAP and the 3-hydroxy-2-phosphonylmethoxypropyl derivatives of adenine (HPMPA) and cytosine (HPMPC, cidofovir)) and PFA. In contrast, the virus strains selected under pressure of PCV were resistant to PCV, ACV, PMEA and PFA; but not BVDU, BVaraU, GCV, HPMPC or HPMPA. Similar patterns of drug susceptibility were noted for the virus strains selected under the pressure of PMEA or PFA, pointing to an alteration in the viral DNA polymerase as basis for the resistant phenotype selected by PCV, as well as PMEA and PFA. In contrast, the resistant phenotype selected by ACV as well as BVDU and BVaraU may be attributed primarily to mutations in the viral TK gene. Our data thus indicate that ACV and PCV select in vitro for different drug-resistant VZV phenotypes; whether this is also the situation in vivo remains to be investigated.

Topics: 2-Aminopurine; Acyclovir; Adenine; Antiviral Agents; Arabinofuranosyluracil; Bromodeoxyuridine; Cidofovir; Cytosine; DNA-Directed DNA Polymerase; Drug Resistance, Multiple, Viral; Drug Resistance, Viral; Foscarnet; Guanine; Herpesvirus 3, Human; Humans; Microbial Sensitivity Tests; Mutation; Organophosphonates; Phenotype; Selection, Genetic; Thymidine Kinase; Viral Proteins

The acyclic nucleoside phosphonate analogue PMEA [9-(2-phosphonylmethoxyethyl)adenine] is a broad spectrum antiviral agent effective against DNA viruses and retroviruses. It is particularly active against the human immunodeficiency virus and, like other phosphonylmethoxyalkyl derivatives, it also inhibits HSV-1, TK- HSV-1 and HSV-2. We have evaluated the therapeutic efficacy of PMEA in the HSV-1 and TK- HSV-1 experimental keratitis models using BVDU (bromovinyldeoxyuridine) as the reference compound. As compared to placebo eyedrops, PMEA 0.2% and BVDU 0.2% eyedrops induced a rapid and significant healing (P less than 0.005) of keratitis caused by TK+ HSV-1. Treatment with PMEA 0.2% eyedrops also reduced the severity of keratitis caused by the TK- HSV-1 (P less than 0.05), whereas BVDU 0.2% eyedrops did not affect the course of TK- HSV-1 keratitis.

Topics: Adenine; Administration, Topical; Animals; Antiviral Agents; Bromodeoxyuridine; Disease Models, Animal; Keratitis, Dendritic; Organophosphonates; Rabbits; Simplexvirus

The phosphonylmethoxyalkyl derivatives HPMPA [(S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine], HPMPC [(S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine] and PMEA [9-(2-phosphonylmethoxyethyl)adenine] were evaluated as 0.2% eyedrops for their efficacy in the treatment of experimental herpes simplex virus type 1 (HSV-1) keratitis in the rabbit model. BVDU 0.2% eyedrops were used as the reference treatment. HPMPA, HPMPC, PMEA and BVDU eyedrops showed a rapid and highly significant healing effect (P less than 0.005) on keratitis caused by TK+ HSV-1 (McIntyre strain) when compared with placebo eyedrops, whereas BVDU treatment did not affect the course of TK- HSV-1 (VMW-1837) keratitis. HPMPA and HPMPC treatment again caused a highly significant healing (P less than 0.005, compared with placebo eyedrops). Although PMEA eyedrops were less effective than HPMPA or HPMPC eyedrops, the effect of PMEA eyedrops was significantly (P less than 0.05) different from the effect of either BVDU or placebo eyedrops.

Topics: Adenine; Animals; Antiviral Agents; Bromodeoxyuridine; Cidofovir; Cytosine; Hempa; Keratitis, Herpetic; Ophthalmic Solutions; Organophosphonates; Organophosphorus Compounds; Rabbits; Simplexvirus; Thymidine Kinase