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O
NH
HO
Bypass the non-productive phosphorylation step
N
O
O
X
PSI-6206
CH
3
O
OH
F
NH
O
HO
P
O
N
O
OH
O
CH
3
O
YMPK
OH
F
O
R
2
NH
O
NH
O
O
R
3
O
2
C
P
O
H
N
O
HO
P
O
P
O
OR
1
O
N
O
OH
OH
O
CH
3
CH
3
OH
F
OH
F
NDPK
O
Phosphoramidate Prodrug
NH
O
O
O
HO
P
O
P
O
P
O
N
O
OH
OH
OH
O
CH
3
OH
F
PSI-6206-TP
Figure 11.4
To produce the active triphosphate metabolite of PSI-6206, a phos-
phoramidate prodrug approach can be used to bypass the phosphor-
ylation step where the kinase does not accept PSI-6206 as a substrate.
the phosphoramidate prodrug strategy had been known for a number of years
and was demonstrated to work in vitro, it had never been demonstrated to be
effective in vivo; presumably, the prodrug moiety decomposed before the intact
prodrug could get to the target cell type or organ. Nevertheless, it seemed to us
that applying this prodrug strategy to treat HCV would be an ideal application
of this methodology because the liver would be the first organ to which the
prodrug would be exposed after absorption. Consequently, we needed to
identify a phosphoramidate prodrug of PSI-6206 that could survive exposure to
the gastrointestinal tract and subsequently undergo the desired decomposition
pathway to reveal the desired uridine monophosphate in hepatocytes.
With our strategy and approach formulated, we prepared an extensive series
of phosphoramidate prodrugs of the 2
0
-F-2
0
-C-methyluridine nucleoside PSI-
6206. Our SAR strategy focused on varying the nature of the carboxylate ester,
phosphate ester, and amino acid side-chain moieties of the phosphoramidate
functionality.
37-39
To assess which of these prodrug candidates possessed the
appropriate properties to progress into in vivo studies, we established an in vitro
testing paradigm that would assess potency,
in vitro safety, and stability
characteristics when
exposed
to
environments
that
simulated
the
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