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

Dae Kee Kim, Namkyu Lee, Young Woo Kim, Kieyoung Chang, Guang Jin Im, Won Son Choi, Key H. Kim

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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 (3.75equiv.) 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. Copyright (C) 1999 Elsevier Science Ltd.

Original languageEnglish
Pages (from-to)419-424
Number of pages6
JournalBioorganic and Medicinal Chemistry
Issue number2
StatePublished - Feb 1999


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