2. Academic Validation
  3. 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

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

  • Bioorg Med Chem Lett. 2017 Sep 15;27(18):4323-4330. doi: 10.1016/j.bmcl.2017.08.029.
François-René Alexandre 1,  Eric Badaroux 2,  John P Bilello 3,  Stéphanie Bot 2,  Tony Bouisset 2,  Guillaume Brandt 2,  Sylvie Cappelle 2,  Christopher Chapron 4,  Dominique Chaves 2,  Thierry Convard 2,  Clément Counor 2,  Daniel Da Costa 2,  David Dukhan 2,  Marion Gay 2,  Gilles Gosselin 5,  Jean-François Griffon 2,  Kusum Gupta 4,  Brenda Hernandez-Santiago 4,  Massimiliano La Colla 4,  Marie-Pierre Lioure 2,  Julien Milhau 2,  Jean-Laurent Paparin 2,  Jérôme Peyronnet 2,  Christophe Parsy 2,  Claire Pierra Rouvière 2,  Houcine Rahali 2,  Rachid Rahali 2,  Aurélien Salanson 2,  Maria Seifer 4,  Ilaria Serra 4,  David Standring 4,  Dominique Surleraux 2,  Cyril B Dousson 2
Affiliations

Affiliations

  • 1 IDENIX an MSD Company, Cap Gamma, 1682 rue de la Valsière, 34189 Montpellier Cedex 4, France. Electronic address: francois-rene.alexandre@merck.com.
  • 2 IDENIX an MSD Company, Cap Gamma, 1682 rue de la Valsière, 34189 Montpellier Cedex 4, France.
  • 3 Merck & Co., Inc., PO Box 4, 770 Sumneytown Pike, West Point, PA 19486, USA; IDENIX Pharmaceuticals, 320 Bent Street - 4th Floor, Cambridge, MA 02139, USA.
  • 4 IDENIX Pharmaceuticals, 320 Bent Street - 4th Floor, Cambridge, MA 02139, USA.
  • 5 UMR 5247 CNRS-Université Montpellier-ENSCM, case courrier 1705, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.
PMID: 28835346 DOI: 10.1016/j.bmcl.2017.08.029
Abstract

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.

Keywords

HCV NS5B polymerase inhibitors; Hepatitis C; Liver delivery; Nucleoside; Pronucleotide; Synthesis and biological evaluation.

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