Synthesis and evaluation of 2-amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine mono- and diesters as potential prodrugs of penciclovir.
2-Amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (7), and its mono- and diesters 8-15 were prepared and evaluated for their potential as prodrugs of penciclovir. Treatment of 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (5) with trimethylamine in THF followed by a reaction of the resulting trimethylammonium chloride salt 6 with KF in DMF afforded 2-amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (7) in 80% yield. Esterification of 7 with an appropriate acid anhydride [Ac2O, (EtCO)2O, (n-PrCO)2O, or (i-PrCO)2O] in DMF in the presence of a catalytic amount of DMAP produced the mono-esters 8-11 in 42-45% yields and diesters 12-15 in 87-99% yields. Of the prodrugs tested in rats, the monoisobutyrate 11 was the most efficiently absorbed and metabolized to 7, showing the mean maximum total concentration of penciclovir (5.5 microg/mL) and 7 (10.8 microg/mL) in the blood was much higher than the mean maximum concentration of penciclovir (11.5 microg/mL) from famciclovir. However, the mean concentrations of penciclovir from 11 were lower than those from famciclovir because of the limited conversion of a major metabolite 7 to penciclovir by adenosine deaminase.
Kim
D K
DK
Life Science Research Center, SK Chemicals, Kyungki-Do, Korea. dkkim@skchemicals.com
Lee
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N
Kim
H T
HT
Im
G J
GJ
Kim
K H
KH
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000737:chemistry; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D004952:Esters; D006147:Guanine; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013057:Spectrum Analysis
D000998:Antiviral Agents; D004952:Esters; D011355:Prodrugs; C053539:penciclovir; D006147:Guanine; D000212:Acyclovir