Antiviral agents prodrugs

U87 Valaciclovir ValACV Valacyclovir. Antiviral agent. Prodrug of acyclovir. Glaxo Wellcome Inc. 

Alkoxyalkanoate esters have been used as prodrugs to improve the oral bioavailability of antiviral agents such as (+)-cyclaradine (carbocyclic arabino-furanosyl adenine) [41]. (+)-Cyclaradine has been shown to be effective against herpes simplex virus in tissue culture at noncytotoxic concentrations. Two prodrugs of (+)-cyclaradine, namely, (+)-cyclaradine-5 -methoxyacetate (CM) and (+)-cyclaradine-5,-ethoxypropionate (CE) (Fig. 2), may be promising candidates... 

These compounds contain the fragment R as an alkyl or aryl moiety. In other words, they result from the esterification of an alcohol or a phenol with nitrous acid, nitric acid, phosphoric acid, sulfuric acid, or sulfamic acid, respectively. Many of the esters to be examined in this chapter must be activated prior to eliciting their effects, e.g., the organic nitrites and nitrates, which act as donors of nitric oxide or an analogous molecule, and phosphates, which are activated by hydrolysis or even by phosphorylation (antiviral agents). Sulfates are very seldom active or used as prodrugs, but they have significance as metabolites and as industrial xenobiotics. 

In an attempt to obtain prodrugs of the antiviral agents 2, 3 -didehydro-2, 3 -dideoxyadenosine (9.33, Base = adeninyl) and 2, 3 -didehydro-2, 3 -dideoxycytosine (9.33, Base = cytosinyl), a variety of phosphorylated derivatives were prepared and tested [91]. Whereas phosphonates (9.31, R = Me or Ph) were inactive, diesters of structure 9.31 (R = MeO or PhO, Base =... 

Dideoxyuridine (ddU) is an antiviral agent that proved ineffective at controlling human immunodeficiency virus type 1 (HIV-1) infection in human T-cells. This ineffectiveness was ascribed to a lack of substrate affinity of ddU for cellular nucleoside kinases, which prevent it from being metabolized to the active 5 -triphosphate. To overcome this problem, bis[(pivaloyloxy)methyl] 2, 3 -dideoxyuridine 5 -monophosphate (9.41) was prepared and shown to be a membrane-permeable prodrug of 2, 3 -di-deoxyuridine 5 -monophosphate (ddUMP, 9.42) [93]. Indeed, human T-cell lines exposed to 9.41 rapidly formed the mono-, di-, and triphosphate of ddU, and antiviral activity was observed. This example again documents... 

Famciclovir is an orally administered prodrug of the antiviral agent penciclovir. Famciclovir is indicated for the treatment of acute herpes zoster (shingles), treatment or suppression of recurrent genital herpes in immunocompetent patients, treatment of recurrent mucocutaneous herpes simplex infections in HIV-infected patients. 

Finally, as a specific example, the regioselective esterification of ribavirin (24) deserves to be discussed (Figure 6.6) [83]. This compound is a powerful antiviral agent used to treat hepatitis C. In order to overcome some significant side effects, it has been suggested that its administration in the form of a prodrug might improve its pharmacokinetic profile. Indeed a series of predinical evaluations showed that the alanine ester 24a possesses improved bioavailability. In... 

Jones, L.A., A. R. Moorman, S. D. Chamberlain, P. deMiranda, D. J. Reynolds, C. L. Burns, andT.A. Krenistky. 1992. Di- and triester prodrugs of the Varicella-Zoster antiviral agent 6-methoxypurine arabinoside. 

As indicated above, bioprecursor prodrugs do not contain a carrier or promoiety but rather contain a latent functionality that is metabolically or chemically transformed to the active drug molecule. The types of activation often involve oxidative activation, reductive activation, phosphorylation, and in some cases chemical activation. Of these, oxidation is commonly. seen, since a number of endogenous enzymes can carry out these transformations. Phosphorylation has been widely exploited in the development of antiviral agents, and many currently available agents depend on this type of activation. 

Ray, A. S., Yang, Z., Chu, C. K., Anderson, K. S. Novel use of a gua-nosine prodrug approach to convert 2, 3 -didehydro-2, 3 -dideoxy-guanosine into a viable antiviral agent. Antimicrob. Agents Chemother. 2002, 46(3), 887-891. 

Many other polymers have been tested as backbonesfor prodrugs. As examples, one may list poly-L-(glutamic acid) for clonidine controlled release (52), hyaluronic acid for hydrocortisone and derivatives (53-55), or the synthetic polyanionic polymer pyran for the antitumor, antibacterial, and antiviral agent muramyl dipeptide (56). Hyaluronic acid and pyran are interesting in the sense that they add a new dimension to the macromolecular prodrug approach. Hyaluronic acid is believed to be potentially useful for the control of infec-... 

Adefovir is an antiviral agent that inhibits hepatitis B virus (HBV) DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. Adefovir is indicated in the treatment of chronic hepatitis B in adults with evidence of active viral replication and evidence of persistent elevations in serum aminotransferases or histologically active disease. Adefovir dipivoxil (9-[2-[bis[(pivaloyloxy)methoxy] phosphinyl]methoxyl]ethyl]adenine, bis-POM PMEA) is a diester prodrug of adefovir, an acyclic phosphonate nucleotide analog of adenosine monophosphate. 

Figure 9.15 An example of the use of a prodrug to improve carrier-mediated transport. Valacyclovir, an L-valine ester prodrug, is transported across intestinal epithelial cell membranes by the HPTl and PEPTl transporters, and is then enzymatically hydrolyzed to the antiviral agent acyclovir before being converted to the true active component, acyclovir triphosphate, in cells.

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