Synthesis and evaluation of amino acid esters of 6-deoxypenciclovir as potential prodrugs of penciclovir Original Research Article

The amino acid ester derivatives of 6-deoxypenciclovir, 11–20, were synthesized as potential prodrugs of penciclovir, and were evaluated for their oral penciclovir bioavailability in mice and rats. Esterification of 6-deoxypenciclovir with N-carbobenzyloxyglycine, -l-alanine, -l-valine, -l-leucine, or -l-isoleucine (3.75 equiv.) using conventional coupling method (DCC/DMAP) afforded the mono-O-ester derivatives 1–5 in 47–55% yields as a mixture of two diastereomers along with the di-O-ester derivatives 6–10 in 20–29% yields. Reductive cleavage of carbobenzyloxy (Cbz) group (10% Pd/C, 1 atmosphere of H2, room temperature in methanol) followed by subsequent treatment of the resulting free amine with methanolic HCl solution provided the mono-O-ester derivatives 11–15 as di-HCl salt in 51–98% yields and the di-O-ester derivatives 16–20 as tri-HCl salt in 65–98% yields. Of the prodrugs tested in mice and rats, 6-deoxypenciclovir O-l-valinate (13), O-l-isoleucinate (15), and O,O-di-glycinate (16) showed significantly higher urinary recovery of penciclovir compared with that of penciclovir, but those are somewhat lower than that of famciclovir. ©