Orally bioavailable acyclic nucleoside phosphonate prodrugs: Adefovir dipivoxil and bis(POC)PMPA

Abstract

This chapter presents that acyclic nucleoside and nucleotide analogs shows substantial clinical utility against a variety of viral infections. Ganciclovir is in use for cytomegalovirus (CMV) infections and prophylaxis in immunocompromised patient populations. Acyclic nucleotide analogs also show potent antiviral activity. Cidofovir (HPMPC), an unusually broad-spectrum antiviral agent with activity against herpes viruses, adenovirus, and papillomavirus, has been approved for therapy of CMV retinitis. Intravenous adefovir (PMEA) has completed phase I/II trials for the treatment of HIV infection. PMPA has shown potent and selective activity against human immunodefficiency vires (HIV) and other retroviruses. It was shown that PMPA was able to prevent SIV infection in macaques even when treatment was initiated as late as 24 h after inoculation. In a phase I/II human clinical study, PMPA given intravenously, was safe and well tolerated and caused a 1.1 log reduction of plasma HIV-RNA levels after only eight doses. Nucleosides and nucleotides usually require conversion to their triphosphate derivative for their biological activity. These active triphosphates target viral or cellular polymerases, inhibiting or terminating the growing polynucleotide chain. Thus, nucleosides have to undergo three distinct phosphorylation steps, consecutively to the mono-, di-, and triphosphates.