20-F-20-C-Methyl Nucleosides and Nucleotides for the Treatment of Hepatitis C Virus: from Discovery to the Clinic - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 255

characteristics, RG7128 showed that nucleosides are positioned to become the
cornerstone of any HCV combination therapy, whether they are added to SOC
or combined with other direct-acting antiviral agents. The unique ecacy and
safety profile, demonstrated high barrier to resistance, and broad genotype
coverage clearly positioned the 2 0 -F-2 0 -C-methyl class of nucleosides as a
platform to further extend the nucleoside strategy and provide new compounds
with improved overall profiles. Consequently, even with the clinical success of
RG7128, we were interested in developing a second-generation compound that
improved on several of the perceived limitations of RG7128. This desire was
driven by the belief that combinations of direct-acting antiviral agents would be
dictating therapeutic regimens in the future, thus potentially displacing the need
for IFN and RBV. To optimally position a nucleoside to take advantage of this
future paradigm, a compound which demonstrated QD dosing and a low pill
burden was desired. Since RG7128 required a 1000mg BID dose to achieve
optimal viral load reduction, investigation of second-generation compounds
was undertaken.
To achieve our objective of identifying a compound that reduced the pill
burden and provided improved PK, we wanted to identify a nucleos(t)ide that
had increased potency over PSI-6130 and provided a high liver/plasma ratio.
The ability to target the liver would reduce the circulating level of nucleos(t)ide
and therefore reduce systemic exposure. At the same time, we wanted to
leverage the exceptional characteristics we had observed with the 2 0 -F-2 0 -C-
methyl class of nucleosides. To achieve this goal, we decided to take advantage
of what was known about the metabolism of PSI-6130. As detailed earlier in
this chapter (Figure 11.3), PSI-6130-MP is metabolized to PSI-6206-MP, the
uridine 5 0 -monophosphate metabolite, which is subsequently metabolized to
the triphosphate of PSI-6206, a potent inhibitor of the HCV RdRp. In addi-
tion, this uridine triphosphate has a significantly long half-life (38 h) in hepa-
tocytes. The problem with PSI-6206 is its inability to be phosphorylated to the
monophosphate precursor of the active triphosphate. Therefore, we speculated
that if we could bypass the nonproductive monophosphorylation step and
deliver a monophosphate to the cell, we could achieve sustained inhibition of
HCV because of the long half-life of the triphosphate. In addition, this long
intracellular half-life might achieve the desired effect of less frequent dosing in
vivo. However, the challenge was to find a way to deliver the monophosphate
intracellularly such that subsequent phosphorylation steps could proceed.
To accomplish the liver targeting aspect of our strategy, we wanted to take
advantage of first-pass metabolism. Since the liver would be the first organ to
which the compound would be exposed after absorption, we wanted to identify
a nucleoside monophosphate prodrug in which the monophosphate of the
parent nucleoside would be revealed upon exposure to liver enzymes. The
phosphoramidate nucleotide prodrug approach described by McGuigan
appeared to have the attributes we desired. 34-36 We speculated that liver
esterases would cleave the terminal carboxylate ester to the acid, thereby trig-
gering the subsequent chain of decomposition events that would ultimately
reveal the desired nucleoside monophosphate (Figure 11.4). However, although