Novel hepatotrophic prodrugs of the antiviral nucleoside 9-(2-phosphonylmethoxyethyl)adenine with improved pharmacokinetics and antiviral activity

The device of new hepatotrophic prodrugs of the antiviral nucleoside 9-(2-p hosphonylmethoxyethyl)adenine (PMEA) with specificity for the asialoglycopr otein receptor on parenchymal liver cells is described. PMEA was conjugated to bi- and trivalent cluster glycosides (K(GN)(2) and K-2 (GN)(3), respect ively) with nanomolar affinity for the asialoglycoprotein receptor. The liv er uptake of the PMEA prodrugs was more than 10-fold higher than that of th e parent drug (52+/-6% and 62+/-3% vs. 4.8+/-0.7% of the injected dose for PMEA) and could be attributed for 90% to parenchymal cells. Accumulation of the PMEA prodrugs in extrahepatic tissue (e.g., kidney, skin) was substant ially reduced. The ratio of parenchymal liver cell-to-kidney uptake-a measu re of the prodrugs therapeutic window-was increased from 0.058 +/- 0.01 for PMEA to 1.86 +/- 0.57 for K(GN)(2)-PMEA and even 2.69 +/- 0.24 for K-2 (GN )(3)-PMEA. Apparently both glycosides have a similar capacity to redirect ( antiviral) drugs to the liver. After cellular uptake, both PMEA prodrugs we re converted into the parent drug, PMEA, during acidification of the lysoso mal milieu (t(1/2) approximate to 100 min), and the released PMEA was rapid ly translocated into the cytosol. The antiviral activity of the prodrugs in vitro was dramatically enhanced as compared to the parent drug (5- and 52- fold for K(GN)(2)-PMEA and K-2 (GN)(3)-PMEA, respectively). Given the 15-fo ld enhanced liver uptake of the prodrugs, we anticipate that the potency in vivo will be similarly increased. We conclude that PMEA prodrugs have been developed with greatly improved pharmacokinetics and therapeutic activity against viral infections that implicate the liver parenchyma (e.g., HBV). I n addition, the significance of the above prodrug concept also extends to d rugs that intervene in other liver disorders such as cholestasis and dyslip idemia.