Synthesis and anti-HIV activity of GS-9148 (2'-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor

  • Bioorg Med Chem Lett. 2008 Feb 1;18(3):1120-3. doi: 10.1016/j.bmcl.2007.11.125.
Constantine G Boojamra  1 ,  Richard L Mackman ,  David Y Markevitch ,  Vidya Prasad ,  Adrian S Ray ,  Janet Douglas ,  Deborah Grant ,  Choung U Kim ,  Tomas Cihlar
Affiliations
  • 1. Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. [email protected]
PMID: 18164198 DOI: 10.1016/j.bmcl.2007.11.125
Abstract

GS-9148 (2'-Fd4AP, 4) has been identified as a nucleoside phosphonate Reverse Transcriptase (RT) inhibitor with activity against wild-type HIV (EC(50)=12 microM). Unlike many clinical RT inhibitors, relevant Reverse Transcriptase mutants (M184V, K65R, 6-TAMs) maintain a susceptibility to 2'-Fd4AP that is similar to wild-type virus. The 2'-fluorine group was rationally designed into the molecule to improve the selectivity profile and in preliminary studies using HepG2 cells, compound 4 showed no measurable effect on mitochondrial DNA content indicating a low potential for mitochondrial toxicity.