Chemistry Reference
In-Depth Information
11.2 The Discovery of PSI-6130
11.2.1 PSI-6130: Rationale and Medicinal Chemistry
For the HCV NS5B RNA-dependent RNA polymerase, there was very little
information available on ribonucleoside analog SAR that would guide a
nucleoside discovery effort. However, it was known that attaching a methyl
group to the 2
0
-b position of a ribonucleoside, as demonstrated by NM107 (1),
produced an active inhibitor of a related RNA virus, the bovine virus diarrhea
virus (BVDV), which was used as a surrogate for HCV.
10
Also, 2
0
-deoxy-2
0
-
fluorocytidine (2) was shown to be a potent HCV inhibitor; however, its
therapeutic potential was suspect because it lacked selectivity for the viral
target over host cells. 2
0
-deoxy-2
0
-fluorocytidine triphosphate showed activity
against both RNA and DNA polymerases. With this limited information in
hand, the 2
0
-deoxy-2
0
-fluoro-2
0
-C-methylcytidine nucleoside PSI-6130 was
prepared and evaluated as an inhibitor of HCV using the subgenomic HCV
replicon assay.
11
PSI-6130 showed potent anti-HCV activity in this assay
(EC
90
ΒΌ
4.5 mM). In fact, had the commonly used BVDV surrogate assay been
used, the activity of PSI-6130 (3) would not have been identified, because PSI-
6130 was shown to be highly specific for HCV over other RNA or DNA
viruses, and was therefore not active against BVDV.
12
NH
2
NH
2
N
N
N
N
O
O
HO
HO
O
O
HO
HO
OH
F
2
1
NH
2
NH
2
N
N
N
N
N
O
O
HO
HO
N
NH
2
O
HO
HO
OH
F
4
3
PSI-6130
In further assessing the 2
0
-F-2
0
-C-methyl class of nucleosides, it became quite
clear that this nucleoside class exhibited some very unique characteristics and
that the combination of a 2
0
-C-b-methyl and 2
0
-a-F substitution imparted both
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