ABSTRACT
We report the design, synthesis and evaluation of a family of ca 50 phosphoramidate ProTides of the potent anti-HCV compound 4'-azidocytidine (R1479), with variation on the ester, amino acid and aryl moiety of the ProTide. Sub-muM inhibitors of HCV emerge. The compounds are all non-cytotoxic in the replicon assay. We herein report detailed SARs for each of the regions of the ProTide.
Subject(s)
Antiviral Agents/chemical synthesis , Chemistry, Pharmaceutical/methods , Cytidine/analogs & derivatives , Hepacivirus/metabolism , Hepatitis C/drug therapy , Technology, Pharmaceutical/methods , Amino Acids/chemistry , Antiviral Agents/pharmacology , Cytidine/chemical synthesis , Cytidine/pharmacology , Drug Design , Drug Evaluation, Preclinical , Humans , Models, Chemical , Prodrugs , Replicon/drug effects , Virus ReplicationABSTRACT
We report the application of our phosphoramidate ProTide technology to the ribonucleoside analogue 4'-azidouridine to generate novel antiviral agents for the inhibition of hepatitis C virus (HCV). 4'-Azidouridine did not inhibit HCV, although 4'-azidocytidine was a potent inhibitor of HCV replication under similar assay conditions. However 4'-azidouridine triphosphate was a potent inhibitor of RNA synthesis by HCV polymerase, raising the question as to whether our phosphoramidate ProTide approach could effectively deliver 4'-azidouridine monophosphate to HCV replicon cells and unleash the antiviral potential of the triphosphate. Twenty-two phosphoramidates were prepared, including variations in the aryl, ester, and amino acid regions. A number of compounds showed sub-micromolar inhibition of HCV in cell culture without detectable cytotoxicity. These results confirm that phosphoramidate ProTides can deliver monophosphates of ribonucleoside analogues and suggest a potential path to the generation of novel antiviral agents against HCV infection. The generic message is that ProTide synthesis from inactive parent nucleosides may be a warranted drug discovery strategy.
Subject(s)
Antiviral Agents/chemical synthesis , Azides/chemical synthesis , Hepacivirus/drug effects , Organophosphorus Compounds/chemical synthesis , Uridine/analogs & derivatives , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Azides/chemistry , Azides/pharmacology , Cell Line, Tumor , Hepacivirus/genetics , Humans , Models, Molecular , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Replicon , Stereoisomerism , Structure-Activity Relationship , Uridine/chemical synthesis , Uridine/chemistry , Uridine/pharmacologyABSTRACT
The lanthanide ion based macrocyclic complexes 1.Ln mimic the hydrophobic nature of ribonucleases, where the lanthanide ions induce the formation of a hydrophobic cavity for 1, giving rise to a large order of magnitude enhancement in the hydrolytic cleavage of HPNP.