TABLE 2.

Comparison of intracellular concentrations of active metabolites of GS-9148, TFV, and ddIa

NRTIMonoamidate prodrugbIncubation concn (nM)Active metabolite concn (pmol/ million cells)c% Inhibition of HIV-1 activity
24 h60 h96 h120 h
GS-9148Ethanolalaninyld2000.850.9079.5NDe
Cyclobutanolalaninyl1001.551.8692.099.3
5004.624.9594.5100
TFVIsopropanolalaninyl200.630.8183.8ND
251.553.6584.491.6
1257.8912.796.1100
ddINAf10,0000.120.2087.293.0
50,0000.670.8096.0100
  • a Intracellular concentrations of the di- or triphosphorylated active metabolites of GS-9148, TFV or ddI are compared to antiviral effects with activated PBMCs infected with HIV-1.

  • b Incubations were done with a stereoisomeric mixture (around phosphorus) of two GS-9148 monoamidate monophenol prodrugs and a single stereoisomer of TFV isopropanolalaninyl monophenol (GS-7340).

  • c Intracellular concentrations of GS-9148-DP, TFV-DP, and ddATP were measured after the incubation of phosphonoamidate prodrugs GS-9148 and TFV or ddI, respectively. Values represent the means of active metabolite levels and antiviral activities from duplicate wells. A difference of less than 15% was observed between duplicate samples, and consistent results were observed across test concentrations.

  • d GS-9131 is a single stereoisomer of the ethanolalaninyl monophenol mixture.

  • e ND, not determined.

  • f NA, not applicable. The nucleoside ddI was incubated in its parent form.