Selective Inhibitors of Hepatitis B Virus Replication

Several nucleoside or nucleoside phosphonate analogues that were discovered as selective inhibitors of the replication of herpesviruses and the human immunodeficiency virus (HIV) have been identified as effective inhibitors of the replication of the hepatitis B virus (HBV). These include (i) dideoxynucleoside analogues that lack hydroxyl groups at both the 2' and 3' of the ribose moeity [e.g. 2',3'-dideoxy-3'-fluorothymidine, FLT], (ii) dioxolane nucleoside analogues in which the 3' carbon of the ribose ring has been replaced by oxygen [e.g. 1-β-D-2,6-diaminopurine dioxolane (DAPD)], (iii) the carbocyclic nucleoside analogues in which the oxygen in the furanose ring is replaced by a carbon [ e.g. cyclopentyl guanine (entecavir)], (iv) 2'-fluorinated pyrimidine nucleoside analogues [e.g. 2'-deoxy-2'-fluoro-1-β-D-arabinofuranosyl-5-iodouracil (FIAC)], (v) iso dideoxynucleoside analogues in which the furanose oxygen is moved to the C3 position (vi) acyclic nucleoside analogues with a truncated open sugar ring structure [e.g. penciclovir], (vii) acyclic nucleoside phosphonate analogues with a phosphonylmethylether group in place of the phosphate moiety [e.g. adefovir], (viii) L-nucleoside analogues which are enantiomers of the ‘natural’ β-D-nucleoside analogues [e.g. lamivudine] and the (ix) cyclobutyl nucleoside analogues which contain a four-membered glycosyl ring [e.g. lobucavir]. Recently also some selective non-nucleoside inhibitors of HBV replication have been identified, these include (i) phenylpropenamide derivatives (ii) iminosugars, a class of cyclic sugar derivatives in which the ring oxygen is replaced by a nitrogen atom and (iii) a class of heteroaryl pyrimidines. Currently only lamivudine and the oral prodrug form of adefovir, i.e. adefovir dipivoxil have been approved for the treatment of chronic HBV infections.