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.
- 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.
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.