ABSTRACT
BACKGROUND: Ribonucleoside analogs possessing a ß-methyl substituent at the 2'-position of the d-ribose moiety have been previously discovered to be potent and selective inhibitors of hepatitis C virus (HCV) replication, their triphosphates acting as alternative substrate inhibitors of the HCV RdRp NS5B. Results/methodology: In this article, the authors detail the synthesis, anti-HCV evaluation in cell-based replicon assays and structure-activity relationships of several phosphoramidate diester derivatives of 2'-C-methylguanosine (2'-MeG). CONCLUSION: The most promising compound, namely the O-[S-(hydroxyl)pivaloyl-2-thioethyl]{abbreviated as O-[(HO)tBuSATE)]} N-benzylamine phosphoramidate diester derivative (IDX184), was selected for further in vivo studies, and was the first clinical pronucleotide evaluated for the treatment of chronic hepatitis C up to Phase II trials.
Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Drug Discovery , Guanosine Monophosphate/analogs & derivatives , Hepacivirus/drug effects , Hepatitis C/drug therapy , Guanosine Monophosphate/chemical synthesis , Guanosine Monophosphate/pharmacology , Humans , Structure-Activity RelationshipABSTRACT
The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as a seven-membered ring sugar moiety, namely 9-(5-deoxy-beta-D-allo-septanosyl)-adenine, is reported. This compound was synthesized in 14 steps from the commercially available D-glycero-D-gulo-1,4-lactone. When evaluated in cell culture experiments against a broad range of viruses, it did not exhibit any significant antiviral effect or cytotoxicity.
Subject(s)
Nucleosides/chemistry , Nucleosides/chemical synthesis , Oligosaccharides/chemistry , Oligosaccharides/chemical synthesis , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Flavivirus/drug effects , Hepacivirus/drug effects , Models, Chemical , Molecular Structure , Nucleosides/pharmacology , Pestivirus/drug effectsABSTRACT
The first example of a nucleoside analogue bearing a 5'-deoxy-beta-D-allo-septanose as the sugar moiety was synthesized and evaluated as a potential inhibitor of several virus replication.