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Small Alkyl
O
NH
R
2
O
O
N
O
O
O
H
P
O
CH
3
R
3
O
HO
F
R
1
Alkyl, Branched Alkyl,
Cycloalkyl
Phenyl, Substituted Phenyl
Figure 11.6
SAR overview of HCV replicon activity for the PSI-6206 5
0
-phosphor-
amidate derivatives is shown.
and produce the desired pharmacological effect. Three compounds, PSI-7672,
PSI-7851, and PSI-8118, were chosen for progression into additional studies that
would result in selection of a preclinical development candidate (see Figure 11.7).
We were particularly interested in further evaluating the PK characteristics of
these compounds in dog and monkey in order to determine which compound
behaved best across species. In addition, we wanted to assess in vitro triphos-
phate levels in primary hepatocytes of rat, dog, and monkey, and compare these
levels to those determined in primary human hepatocytes. These in vitro and in
vivo studies would provide the necessary comparative data to choose the com-
pound with the best overall profile.
Of the three compounds, PSI-7851 consistently outperformed the others
across species in both the in vitro and in vivo assessment of triphosphate for-
mation. In vivo toxicology assessment in rats and evaluation of their ability to
induce bone marrow toxicity were not able to differentiate further between the
three candidates. Each of the compounds exhibited no observable adverse
effects levels of 41800mg kg
1
when dosed orally to rats, and none of the
compounds demonstrated effects on bone marrow cells in vitro at concentra-
tions up to 50 mM. Its superior ecacy relative to RG7128, strong safety
profile, and demonstrated superior PK profile (including formation of high
levels of triphosphate) positioned PSI-7851 as the clear winner. Consequently,
PSI-7851 was selected as the preclinical development candidate.
11.4.2 PSI-7851 Metabolic Characterization
In deciding to take PSI-7851 into development, a question remained on whe-
ther we would get therapeutic levels of the active PSI-6206-TP in human liver.
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