Synthesis and evaluation of amino acid esters of 6-deoxypenciclovir as potential prodrugs of penciclovir.

Abstract 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 H 2 , 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. ©