Preclinical investigation of L-FMAU as an anti-hepatitis B virus agent.
Preclinical aspects of a potent anti-hepatitis B virus (HBV) L-nucleoside, 1-(2-fluoro-5-methyl-beta-L-arabino-furanosyl)uracil (L-FMAU) are described. L-FMAU was prepared from L-ribose derivatives via either L-xylose or L-arabinose. L-FMAU shows potent antiviral activity against hepatitis B virus (EC50 5.0 microM in H1 cells) with high selectivity in vitro. L-FMAU is not incorporated into mitochondrial DNA and no significant lactic acid production was observed in vitro. L-FMAU is phosphorylated by thymidine kinase as well as deoxycytidine kinase, ultimately to the triphosphate, which inhibits HBV DNA polymerase as the mechanism of antiviral action. Preliminary in vivo toxological studies suggest no apparent toxicity for 30 days at 50 mg/kg/day in mice and for 3 months in woodchucks (10 mg/kg/day). L-FMAU also has respectable bioavailability in rats. L-FMAU shows potent anti-HBV activity in vivo against woodchuck hepatitis virus in chronically infected woodchucks and there is no significant virus rebound after cessation of the drug treatment.
Chu
C K
CK
University of Georgia College of Pharmacy, Athens 30602, USA. DChu@RX.UGA.EDU
Boudinot
F D
FD
Peek
S F
SF
Hong
J H
JH
Choi
Y
Y
Korba
B E
BE
Gerin
J L
JL
Cote
P J
PJ
Tennant
B C
BC
Cheng
Y C
YC
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D001086:Arabinofuranosyluracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D001682:Biological Availability; D002460:Cell Line; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004372:Ducks; D018347:Hepadnaviridae Infections / Q000188:drug therapy / Q000821:virology; D015611:Hepatitis B Virus, Duck / Q000187:drug effects; D017919:Hepatitis B Virus, Woodchuck / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects*; D019694:Hepatitis B, Chronic / Q000188:drug therapy / Q000821:virology; D019344:Lactic Acid / Q000097:blood / Q000378:metabolism; D007928:Lethal Dose 50; D008392:Marmota; D051379:Mice; D010766:Phosphorylation; D051381:Rats; D013937:Thymidine Kinase / Q000378:metabolism
D000998:Antiviral Agents; D001086:Arabinofuranosyluracil; D019344:Lactic Acid; D013937:Thymidine Kinase; D003842:Deoxycytidine Kinase; C034935:clevudine