Synthesis and evaluation of amino acid esters of 6-deoxypenciclovir as potential prodrugs of penciclovir.
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.
Kim
D K
DK
Life Science Research Center, SK Chemicals, Suwon-Si, Kyungki-Do, Korea. dkkim@skchemicals.com
Lee
N
N
Kim
Y W
YW
Chang
K
K
Im
G J
GJ
Choi
W S
WS
Kim
K H
KH
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
C108016:6-deoxypenciclovir; D000998:Antiviral Agents; D004952:Esters; C053539:penciclovir; D006147:Guanine; D000212:Acyclovir