The Discovery of GS-9131, an Amidate Prodrug of a Novel Nucleoside Phosphonate HIV Reverse Transcriptase Inhibitor - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 218

Figure 10.2

Intracellular metabolic metabolic pathway of N(t)RTI 2 compared to
NRTI 3.

first metabolite in the activation pathway of deoxyadenosine. Therefore, only
two kinases are required to generate the active diphosphophosphonate (1-DP)
metabolite which is equivalent to the deoxynucleoside triphosphate. Often the
first metabolism step is rate limiting in the activation of nucleosides to their
monophosphates, so the phosphonate effectively bypasses this step. A second
distinction of the nucleoside phosphonates is that they are charged at physio-
logical pH and therefore require prodrugs, such as the disoproxil ester groups
found in 2, to effectively cross the cell membrane. However, once the prodrug
penetrates the cell, and is cleaved by intracellular esterases to release the
phosphonic acid, the stability of the P-C bond to further cleavage by enzymes
prevents the generation of a neutral species, effectively trapping the charged
diacid in the cell. The combination of enhanced phosphonate stability and
inecient removal from the cell leads to prolonged intracellular levels of the
diphosphate metabolite 1-DP. Clinically, the intracellular half life of 1-DP has
been measured to exceed 150 h in activated lymphoid cells, a property that
clearly favors administration of prodrug 2 on a qd regimen. 7 A final point