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

Autor:	François-René Alexandre, Eric Badaroux, John P. Bilello, Stéphanie Bot, Tony Bouisset, Guillaume Brandt, Sylvie Cappelle, Christopher Chapron, Dominique Chaves, Thierry Convard, Clément Counor, Daniel Da Costa, David Dukhan, Marion Gay, Gilles Gosselin, Jean-François Griffon, Kusum Gupta, Brenda Hernandez-Santiago, Massimiliano La Colla, Marie-Pierre Lioure, Julien Milhau, Jean-Laurent Paparin, Jérôme Peyronnet, Christophe Parsy, Claire Pierra Rouvière, Houcine Rahali, Rachid Rahali, Aurélien Salanson, Maria Seifer, Ilaria Serra, David Standring, Dominique Surleraux, Cyril B. Dousson
Rok vydání:	2017
Předmět:	0301 basic medicine viruses Clinical Biochemistry Pharmaceutical Science Hepacivirus Microbial Sensitivity Tests Viral Nonstructural Proteins 01 natural sciences Biochemistry Antiviral Agents 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship RNA polymerase Drug Discovery Animals Humans Replicon Enzyme Inhibitors Molecular Biology NS5B Uridine Polymerase chemistry.chemical_classification biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Organic Chemistry virus diseases Phosphoramidate DNA-Directed RNA Polymerases Prodrug Molecular biology digestive system diseases 0104 chemical sciences 030104 developmental biology Enzyme chemistry Liver biology.protein Hepatocytes Molecular Medicine Uridine Monophosphate
Zdroj:	Bioorganicmedicinal chemistry letters. 27(18)
ISSN:	1464-3405
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e8795b8e1e924d640806c19eaa1d19ab https://pubmed.ncbi.nlm.nih.gov/28835346 Zobrazit plný text záznamu Full Text from ScienceDirect