Evaluation of 2'-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase

Jay P Parrish; Sharon K Lee; Constantine G Boojamra; Hon Hui; Darius Babusis; Brandon Brown; I-hung Shih; Joy Y Feng; Adrian S Ray; Richard L Mackman

doi:10.1016/j.bmcl.2013.03.095

Evaluation of 2'-α-fluorine modified nucleoside phosphonates as potential inhibitors of HCV polymerase

Bioorg Med Chem Lett. 2013 Jun 1;23(11):3354-7. doi: 10.1016/j.bmcl.2013.03.095. Epub 2013 Apr 2.

Authors

Jay P Parrish¹, Sharon K Lee, Constantine G Boojamra, Hon Hui, Darius Babusis, Brandon Brown, I-hung Shih, Joy Y Feng, Adrian S Ray, Richard L Mackman

Affiliation

¹ Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. [email protected]

PMID: 23639543
DOI: 10.1016/j.bmcl.2013.03.095

Abstract

Ribonucleoside phosphonate analogues containing 2'-α-fluoro modifications were synthesized and their potency evaluated against HCV RNA polymerase. The diphosphophosphonate (triphosphate equivalent) adenine and cytidine analogues displayed potent inhibition of the HCV polymerase in the range of 1.9-2.1 μM, but only modest cell-based activity in the HCV replicon. Pro-drugs of the parent nucleoside phosphonates improved the cell-based activity.

Publication types

Evaluation Study

MeSH terms

Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry*
Antiviral Agents / pharmacology
Cell Line
DNA-Directed RNA Polymerases / antagonists & inhibitors*
DNA-Directed RNA Polymerases / metabolism
Drug Evaluation, Preclinical
Fluorine / chemistry*
Hepacivirus / enzymology*
Humans
Organophosphonates / chemical synthesis
Organophosphonates / chemistry*
Organophosphonates / pharmacology
Ribonucleosides / chemistry*
Virus Replication / drug effects

Substances

Antiviral Agents
Organophosphonates
Ribonucleosides
Fluorine
DNA-Directed RNA Polymerases