Design, synthesis, and anti-HIV activity of 4'-modified carbocyclic nucleoside phosphonate reverse transcriptase inhibitors

  • Bioorg Med Chem. 2009 Feb 15;17(4):1739-46. doi: 10.1016/j.bmc.2008.12.028.
Constantine G Boojamra  1 ,  Jay P Parrish ,  David Sperandio ,  Ying Gao ,  Oleg V Petrakovsky ,  Sharon K Lee ,  David Y Markevitch ,  Jennifer E Vela ,  Genevieve Laflamme ,  James M Chen ,  Adrian S Ray ,  Abraham C Barron ,  Mark L Sparacino ,  Manoj C Desai ,  Choung U Kim ,  Tomas Cihlar ,  Richard L Mackman
Affiliations
PMID: 19179082 DOI: 10.1016/j.bmc.2008.12.028
Abstract

A diphosphate of a novel cyclopentyl based nucleoside phosphonate with potent inhibition of HIV Reverse Transcriptase (RT) (20, IC(50)=0.13 microM) has been discovered. In Cell Culture the parent phosphonate diacid 9 demonstrated Antiviral activity EC(50)=16 microM, within two-fold of GS-9148, a prodrug of which is currently under clinical investigation, and within 5-fold of tenofovir (PMPA). In vitro cellular metabolism studies using 9 confirmed that the active diphosphate metabolite is produced albeit at a lower efficiency relative to GS-9148.