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Bioorg Med Chem Lett ; 27(18): 4323-4330, 2017 09 15.
Article in English | MEDLINE | ID: mdl-28835346

ABSTRACT

Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-ß-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.


Subject(s)
Antiviral Agents/pharmacology , DNA-Directed RNA Polymerases/antagonists & inhibitors , Drug Discovery , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Uridine Monophosphate/analogs & derivatives , Uridine/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , DNA-Directed RNA Polymerases/metabolism , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Hepatocytes/drug effects , Hepatocytes/virology , Humans , Liver/drug effects , Liver/virology , Mice , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity Relationship , Uridine/chemical synthesis , Uridine/chemistry , Uridine Monophosphate/chemical synthesis , Uridine Monophosphate/chemistry , Uridine Monophosphate/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/metabolism
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