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. Epub 2007 Dec 5.

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.

MeSH terms

  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / pharmacology*
  • DNA, Mitochondrial / drug effects
  • Fluorine / chemistry*
  • Guanosine / analogs & derivatives*
  • Guanosine / chemical synthesis*
  • Guanosine / chemistry
  • Guanosine / pharmacology*
  • HIV Reverse Transcriptase / genetics
  • Humans
  • Molecular Structure
  • Nucleosides / chemical synthesis*
  • Nucleosides / chemistry
  • Nucleosides / pharmacology*
  • Organophosphonates / chemical synthesis*
  • Organophosphonates / chemistry
  • Organophosphonates / pharmacology*
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Zidovudine / pharmacology

Substances

  • Anti-HIV Agents
  • DNA, Mitochondrial
  • Nucleosides
  • Organophosphonates
  • Reverse Transcriptase Inhibitors
  • Guanosine
  • Fluorine
  • Zidovudine
  • HIV Reverse Transcriptase