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.