Discovery and Synthesis of C-Nucleosides as Potential New Anti-HCV Agents

  • ACS Med Chem Lett. 2014 Apr 10;5(6):679-84. doi: 10.1021/ml500077j.
Alistair G Draffan  1 ,  Barbara Frey  1 ,  Brett Pool  1 ,  Carlie Gannon  1 ,  Edward M Tyndall  1 ,  Michael Lilly  1 ,  Paula Francom  1 ,  Richard Hufton  1 ,  Rosliana Halim  1 ,  Saba Jahangiri  1 ,  Silas Bond  1 ,  Van T T Nguyen  1 ,  Tyrone P Jeynes  1 ,  Veronika Wirth  1 ,  Angela Luttick  1 ,  Danielle Tilmanis  1 ,  Jesse D Thomas  1 ,  Melinda Pryor  1 ,  Kate Porter  1 ,  Craig J Morton  1 ,  Bo Lin  1 ,  Jianmin Duan  2 ,  George Kukolj  2 ,  Bruno Simoneau  2 ,  Ginette McKercher  2 ,  Lisette Lagacé  2 ,  Ma'an Amad  2 ,  Richard C Bethell  2 ,  Simon P Tucker  1
Affiliations
  • 1. Biota Scientific Management Pty. Ltd. , 10/585 Blackburn Road, Notting Hill, Victoria 3168, Australia.
  • 2. Research and Development, Boehringer Ingelheim (Canada), Ltd. , 2100 rue Cunard, Laval, Québec H7S 2G5, Canada.
Abstract

Nucleoside analogues have long been recognized as prospects for the discovery of direct acting antivirals (DAAs) to treat hepatitis C virus because they have generally exhibited cross-genotype activity and a high barrier to resistance. C-Nucleosides have the potential for improved metabolism and pharmacokinetic properties over their N-nucleoside counterparts due to the presence of a strong carbon-carbon glycosidic bond and a non-natural heterocyclic base. Three 2'CMe-C-adenosine analogues and two 2'CMe-guanosine analogues were synthesized and evaluated for their anti-HCV efficacy. The nucleotide triphosphates of four of these analogues were found to inhibit the NS5B polymerase, and Adenosine analogue 1 was discovered to have excellent pharmacokinetic properties demonstrating the potential of this drug class.

Keywords
C-Nucleoside; HCV; NS5B polymerase.