title: 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-carbobenzyl-oxyglycine, -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 HCI 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.
authors.affiliation: Life Science Research Center, SK Chemicals, Suwon-Si, Kyungki-Do, Korea. dkkim@skchemicals.com
authors.forename: D K
authors.initials: DK
authors.lastname: Kim
authors.forename: N
authors.initials: N
authors.lastname: Lee
authors.forename: Y W
authors.initials: YW
authors.lastname: Kim
authors.forename: K
authors.initials: K
authors.lastname: Chang
authors.forename: G J
authors.initials: GJ
authors.lastname: Im
authors.forename: W S
authors.initials: WS
authors.lastname: Choi
authors.forename: K H
authors.initials: KH
authors.lastname: Kim
mesh_terms: D000212:Acyclovir / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004952:Esters / Q000138:chemical synthesis*; D006147:Guanine; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008956:Models, Chemical; D051381:Rats; D013053:Spectrophotometry
chemical_list: C108016:6-deoxypenciclovir; D000998:Antiviral Agents; D004952:Esters; C053539:penciclovir; D006147:Guanine; D000212:Acyclovir