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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. 2017
François-René Alexandre, and
Eric Badaroux, and
John P Bilello, and
Stéphanie Bot, and
Tony Bouisset, and
Guillaume Brandt, and
Sylvie Cappelle, and
Christopher Chapron, and
Dominique Chaves, and
Thierry Convard, and
Clément Counor, and
Daniel Da Costa, and
David Dukhan, and
Marion Gay, and
Gilles Gosselin, and
Jean-François Griffon, and
Kusum Gupta, and
Brenda Hernandez-Santiago, and
Massimiliano La Colla, and
Marie-Pierre Lioure, and
Julien Milhau, and
Jean-Laurent Paparin, and
Jérôme Peyronnet, and
Christophe Parsy, and
Claire Pierra Rouvière, and
Houcine Rahali, and
Rachid Rahali, and
Aurélien Salanson, and
Maria Seifer, and
Ilaria Serra, and
David Standring, and
Dominique Surleraux, and
Cyril B Dousson
IDENIX an MSD Company, Cap Gamma, 1682 rue de la Valsière, 34189 Montpellier Cedex 4, France. Electronic address: francois-rene.alexandre@merck.com.
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.
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