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

A diphosphate of a novel cyclopentyl based nucleoside phosphonate with potent inhibition of HIV reverse transcriptase (RT) (20, IC50 = 0.13 μM) has been discovered. In cell culture the parent phosphonate diacid 9 demonstrated antiviral activity EC50 = 16 μM, 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.

A series of 4′-modified carbocyclic nucleoside phosphonates were synthesized and found to be potent submicromolar inhibitors of HIV reverse transcriptase.Figure optionsDownload as PowerPoint slide