Alkoxyalkyl prodrugs of acyclic nucleoside phosphonates enhance oral antiviral activity and reduce toxicity: Current state of the art

Abstract

Although the acyclic nucleoside phosphonates cidofovir, adefovir and tenofovir are approved for treating human cytomegalovirus, hepatitis B and HIV infections, respectively, their utility is limited by low oral bioavailability, renal toxicity and poor cell penetration. Research over the past decade has shown that these undesirable features can be eliminated by esterifying the compounds with an alkoxyalkyl group, in effect disguising them as lysophospholipids. In this modified form, the drugs are readily taken up in the gastrointestinal tract and have a prolonged circulation time in plasma. The active metabolite also has a long half life within cells, permitting infrequent dosing. Because these modified drugs are not recognized by the transport mechanisms that cause the accumulation of acyclic nucleoside phosphonates in renal tubular cells, they lack nephrotoxicity. Alkoxyalkyl esterification also markedly increases the in vitro antiviral activity of acyclic nucleoside phosphonates by improving their delivery into cells. For example, an alkoxyalkyl ester of cyclic-cidofovir, a less soluble compound, retains antiviral activity for 3 months following a single intravitreal injection. Two of these novel compounds, hexadecyloxypropyl-cidofovir (CMX-001) and hexadecyloxypropyl-tenofovir (CMX-157) are now in clinical development. This article focuses on the hexadecyloxypropyl and octadecyloxyethyl esters of cidofovir and (S)-HPMPA, describing their synthesis and the evaluation of their in vitro and in vivo activity against a range of orthopoxviruses, herpesviruses, adenoviruses and other double-stranded DNA viruses. The extension to other nucleoside phosphonate antivirals is highlighted, demonstrating that this novel approach can markedly improve the medicinal properties of these drugs.

Antiviral Drug Resistance of Human Cytomegalovirus

“…It was FDA approved in 1996 for intravenous use. An experimental lipid-conjugated oral prodrug formulation is in clinical trials (95).…”

A 40-Year Journey in Search of Selective Antiviral Chemotherapy*

“…To increase cidofovir's oral bioavailability and at the same time reduce its nephrotoxicity, several alkoxyalkyl derivatives have been prepared, the most prominent of which are octadecyloxyethyl (ODE) and hexadecyloxypropyl (HDP) (41,78). The ODE and HDP derivatives of (S)-HPMPC [or (S)-HPMPA] should, in principle, be applicable in the oral treatment of all infections due to viruses sensitive to (S)-HPMPC or (S)-HPMPA, such as herpes, adeno-, pox-, polyoma-, and papillomavirus infections.…”

Renal Concerns in the Treatment of Chronic Hepatitis B with Tenofovir

“…Since 2008, it has been indicated for the treatment of adults with chronic HBV infection or HIV/HBV co-infection. It is administered orally as the prodrug TDF or tenofovir alafenamide (5,6). Following oral administration, TDF is essentially completely absorbed in the gastrointestinal tract and peak plasma concentrations are reached within 0.25-1.5 h. The prodrug moiety of TDF is efficiently cleaved and minimal intact prodrug is observed in systemic circulation.…”