Prodrugs antiviral

Arimilli MN, Kim CU, Dougherty J, Mulato A, Oliyai R, Shaw JP, Cundy KC, Bischofberger N. Synthesis, in vitro biological evaluation and oral bioavailability of 9-[2-(phosphonomethoxy)propyl] adenine (PMPA) prodrugs. Antiviral Chem. Chemother., 1997, 8(6), 557-564. 

Dong SD, Lin C, Schroeder M (2013) Synthesis and evaluation of a new phosphorylated ribavirin prodrug. Antiviral Res 99 18-26... 

Lethal drug interactions of new antiviral, sorivudin [l-(3-D-arabinofuranosyl-( )-5-(2-bromvinyl)uracil], with anticancer prodrugs of 5-fluorouracil structure 97YZ910. 

De Clercq E, Eield H J (2006) Antiviral prodrugs - the development of successful prodrug strategies for antiviral chemotherapy. Brit J Pharmacol 147 1-11 De Clercq E, Hol A, Rosenberg I, Sakuma T, Balzarini J, Maudgal PC (1986) A novel selective broad-spectrum anti-DNA virus agent. Nature 323 464 67 De Clercq E, Sakuma T, Baba M, Pauwels R, Balzarini J, Rosenberg I, Hol A (1987) Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. Antiviral Res 8 261-272... 

Kre merov4 M, H0I5 A, Pohl R, Masojidkovi M, Andrei G, Naesens L, Neyts J, Balzarini J, De Clercq E, Snoeck R (2007b) Ester prodrugs of cychc l-(S)-[3-hyioxy-2-(phosphonomethoxy)propyl]-5-azacytosine synthesis and antiviral activity. J Med Chem 50 5765-5772... 

Starrett JE Jr, Tortolani DR, Hitchcock MJM, Martin JC, Mansuri MM. Synthesis and in vitro evaluation of a phosphonate prodrug bis(pivaloyloxy-methyl)-9-(2-phosphonylmethoxyethyl)adenine. Antiviral Res 1992 19 267-273. 

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... 

Naesens, L., Clercq, E. de, Van den Mooter, G., Kinget, R., Augustijns, P., Inhibition of intestinal metabolism of the antiviral ester prodrug bis(POC)-PMPA by nature-identical fruit extracts as a strategy to enhance its oral absorption an in vitro study, Pharm. Res. 1999, 16, 1035-1040. 

Annaert P, Tukker JJ, Van Gelder J, Naesens L, de Clercq E, Van den Mooter G, Kinget R, Augustijns P (2000) In vitro, ex vivo, and in situ intestinal absorption characteristics of the antiviral ester prodrug adefovir dipivoxil. J Pharm Sci 89 1054-1062. 

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... 

A more complex pathway of activation is seen in N-amino acid derivative of phosphoramidic acid diesters of antiviral nucleosides, as exemplified by prodrugs of stavudine (9.79, Fig. 9.14) [153 -155], The activation begins with a carboxylesterase-mediated hydrolysis of the terminal carboxylate. This is followed by a spontaneous nucleophilic cyclization-elimination, which forms a mixed-anhydride pentacycle (9.80, Fig. 9.14). The latter hydrolyzes spontaneously and rapidly to the corresponding phosphoramidic acid monoester (9.81, Fig. 9.14), which can then be processed by phosphodiesterase to the nucleoside 5 -monophosphate, and by possible further hydrolysis to the nucleoside. 

S. Benzaria, H. Pelicano, R. Johnson, G. Maury, J. L. Imbach, A. M. Aubertin, G. Obert, G. Gosselin, Synthesis, in vitro Antiviral Evaluation, and Stability Studies of Bis(S-acyl-2-thioethyl) Ester Derivatives of 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA) as Potential PMEA Prodrugs with Improved Oral Bioavailability , J. Med. Chem. 1996, 39, 4958-4965. 

G. D. Kini, J. R. Beadle, K. A. Aldern, K. Y. Hostetler, Propanediol Phospholipid Prodrugs of Foscarnet (PFA) Synthesis and Structure-Antiviral Activity Relationships , in Abstracts of the 211th American Chemical Society National Meeting, Division of Medicinal Chemistry , New Orleans, LA, March 24-28, 1996, Abstract No. 172. 

---