The discovery of IDX21437: Design, synthesis and antiviral evaluation of 2′-α-chloro-2′-β-C-methyl branched uridine pronucleotides as potent liver-targeted HCV polymerase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2017-09, Vol.27 (18), p.4323-4330
• Main Authors: Alexandre, François-René, Badaroux, Eric, Bilello, John P., Bot, Stéphanie, Bouisset, Tony, Brandt, Guillaume, Cappelle, Sylvie, Chapron, Christopher, Chaves, Dominique, Convard, Thierry, Counor, Clément, Da Costa, Daniel, Dukhan, David, Gay, Marion, Gosselin, Gilles, Griffon, Jean-François, Gupta, Kusum, Hernandez-Santiago, Brenda, La Colla, Massimiliano, Lioure, Marie-Pierre, Milhau, Julien, Paparin, Jean-Laurent, Peyronnet, Jérôme, Parsy, Christophe, Pierra Rouvière, Claire, Rahali, Houcine, Rahali, Rachid, Salanson, Aurélien, Seifer, Maria, Serra, Ilaria, Standring, David, Surleraux, Dominique, Dousson, Cyril B.
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Chemical Sciences; DNA-Directed RNA Polymerases; DNA-Directed RNA Polymerases - antagonists & inhibitors; DNA-Directed RNA Polymerases - metabolism; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; HCV NS5B polymerase inhibitors; Hepacivirus; Hepacivirus - drug effects; Hepacivirus - enzymology; Hepatitis C; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - virology; Humans; Liver; Liver - drug effects; Liver - virology; Liver delivery; Mice; Microbial Sensitivity Tests; Molecular Structure; Nucleoside; Pronucleotide; Structure-Activity Relationship; Synthesis and biological evaluation; Uridine; Uridine - chemical synthesis; Uridine - chemistry; Uridine - pharmacology; Uridine Monophosphate; Uridine Monophosphate - analogs & derivatives; Uridine Monophosphate - chemical synthesis; Uridine Monophosphate - chemistry; Uridine Monophosphate - pharmacology; Viral Nonstructural Proteins; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2017.08.029

[Display omitted] Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2′-α-chloro-2′-β-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.