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O
R
2
O
NH
N
O
O
R
3
H
P
O
O
O
O
R
1
F
HO
R
3
=
PSI-7851
R
2
=
CH
3
R
1
=
PSI-7672
R
1
=
R
2
=
CH
3
R
3
=
CH
3
PSI-8118
R
1
=
R
2
=
CH
3
R
3
=
F
Figure 11.7
The three lead PSI-6206 phosphoramidate derivatives, PSI-7851, 7976,
and 8118, are shown. They provided the best overall profile after lead
optimization assessment.
We had in vivo animal data to support our hypothesis, but similar experiments
in humans to assess exposure were not practical. So we needed to determine the
potential for PSI-7851 to generate PSI-6206-TP in human liver cells. Although
the mechanism by which phosphoramidate prodrugs are metabolized to the
active triphosphate has been reported, to our knowledge no one has demon-
strated that a phosphoramidate nucleotide prodrug could be converted to a
nucleoside triphosphate in human liver.
34-36
We speculated that the first step in
the activation pathway of PSI-7851 involved the hydrolysis of the carboxyester
moiety and that this hydrolytic step was catalyzed by human cathepsin A and
carboxyesterase 1 (Figure 11.8). Hydrolysis of the ester was then likely followed
by a putative nucleophilic attack of the phosphorus by the carboxyl group,
resulting in the spontaneous elimination of phenol and producing an inter-
mediate diacid metabolite. We were able to substantiate the above mechanistic
hypothesis both by demonstrating through Western blot analysis that sig-
nificant levels of both cathepsin A and carboxyesterase 1 were expressed in
primary human hepatocytes, and through identifying the intermediate diacid
metabolite as PSI-352707 (Figure 11.8).
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