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 235

since both compounds would presumably be dependent on the same intracel-
lular phosphorylation enzymes. However, no antagonism of the intracellular
pharmacology was found when combining 22 with 1 at suprapharmacologic
concentrations or co-incubation of prodrugs 2 and 32 at 1 mM in activated
PBMCs. 34 It should be noted that, under these incubation conditions, the
concentration of metabolites of 2 exceed those observed in patient PBMCs by
more than 100-fold. This result suggests that the adenosine phosphorylating
enzymes have a high capacity and can accommodate co-administration of
adenosine analogs, a result that is supported by the additive to slightly syner-
gistic antiviral activity observed when combining 1 and 22. 29 Additionally,
metabolites of 1 have been reported to antagonize the catabolism of ddI (5) via
inhibition of purine nucleoside phosphorylase. Studies have shown that 22 and
its metabolites show a low inhibition for purine nucleoside phosphorylase and
therefore a low potential to impact the pharmacokinetics of 5. In summary, the
combined data for 22 and its prodrug 32, regarding interactions with renal
transporters and intracellular pharmacokinetics when co-administered with
other agents, supported a promising short- and long-term in vivo toxicity profile
and enabled the compound to be selected for clinical development.
10.4 Conclusion
The discovery program for 22 and its amidate prodrug 32 was ultimately suc-
cessful. The target profile established at the initiation of the program, although
stringent, was met on all counts. The novel N(t)RTI 22 demonstrated good
potency toward HIV RT, and the rational design of a 2 0 -F group enabled
selectivity to be significantly improved. The resistance profile of 22 was estab-
lished from broad-based patient isolate screening to be very favorable compared
to all the approved drugs in the N(t)RTI class. Application of amidate prodrugs
cleaved by Cat A allowed for 22 to be e ciently targeted to the desired lymphatic
cells in vivo. In beagle dogs, a single oral dose of prodrug 32 delivered 22 and its
active diphosphate metabolite at levels exceeding the RT IC 50 and the active
metabolite levels persisted for 424 h, favoring the potential for a qd therapeutic.
Prodrug 32 therefore proceeded unabated into clinical development until its
development was put on hold in early 2009. Over the course of the program,
Atripla t established itself as the dominant first-line therapy for HIV patients
given the increased convenience of the once-daily fixed-dose option. This con-
venient regimen also led to changes in the patterns of N(t)RTI patient resistance.
For example, the clinical manifestation of K65R-resistant strains, that were of
concern in the initial years following the approval of 2, have not materialized. For
this, and other reasons, more focus has now been placed on the development of
fixed-dose qd therapies that contain drugs targeted toward HIV integrase or other
new antiviral enzyme targets. It is anticipated that this strategy may provide the
next significant leap forward in HIV treatment options. Clinical trails are already
ongoing to address these questions and as the results emerge, the suitability and
need to develop 32 may well change. The final chapter on 32 may not be written.