Synthesis, metabolic stability and antiviral evaluation of various alkoxyalkyl esters of cidofovir and 9-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine

Abstract

Alkoxyalkyl esters of cidofovir (CDV) are orally active agents which inhibit the replication of a variety of double stranded DNA (dsDNA) viruses including variola, vaccinia, ectromelia, herpes simplex virus, cytomegalovirus, adenovirus and others. One of these compounds, hexadecyloxypropyl-CDV (HDP-CDV, CMX001) is in clinical development for prevention and treatment of poxvirus infection, vaccination complications, and for infections caused by cytomegalovirus, adenovirus, herpesviruses and other dsDNA viruses. This class of lipid analogs is potentially prone to undergo omega oxidation of the alkyl moiety which can lead to a short chain carboxylic acid lacking antiviral activity. To address this issue, we synthesized a series of alkoxyalkyl or alkyl glycerol esters of CDV and (S)-HPMPA having modifications in the structure of the alkyl residue. Antiviral activity was assessed in cells infected with vaccinia, cowpox or ectromelia viruses. Metabolic stability was determined in S9 membrane fractions from rat, guinea pig, monkey and human liver. All compounds had substantial antiviral activity in cells infected with vaccinia, cowpox or ectromelia. Metabolic stability was lowest in monkey liver S9 incubations where rapid disappearance of HDP-CDV and HDP-(S)-HPMPA was noted. Metabolic stability in monkey preparations increased substantially when a ω-1 methyl group (15-methyl-HDP-CDV) or a terminal cyclopropyl residue (14-cyclopropyl-tetradecyloxypropyl-CDV) was present in the alkyl chain. The most stable compound was 1-O-octadecyl-2-O-benzyl-sn-glycero-3-CDV (ODBG-CDV) which was not metabolized extensively by monkey liver S9. In rat, guinea pig or human liver S9 incubations, most of the modified antiviral compounds were considerably more stable.

Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia

“…In contrast, HDP-adefovir showed a lower cytotoxic activity compared to adefovir-DP and ODE-adefovir in all cases. This difference may be due to variability in the propensity to omega oxidation observed for the different alkyloxyalkyl direvatives, leading to the formation of metabolites lacking activity [21]. …”

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…Based on the biological results, including stability in plasma and in liver and intestinal homogenates, it was hypothesized that breakdown occurs via an esterase-mediated hydrolysis of the carboxylate ester of the salicylate, followed by complete release of the drug [104]. The use of long lipid esters also has been investigated [105]. For example, the efficacy of phospholipid esters of cyclic cidofovir (e.g.…”

Adenovirus DNA Replication

“…Current efforts are concentrated on optimizing the formulation of cidofovir and the development of new derivatives (Toth et al 2008;Paolino et al 2011;Ruiz et al 2011). In addition, high-throughput screening for inhibitors of viral replication can identify new compounds that function as broad-spectrum antiviral agents.…”