A. Gopalsamy et al. / Bioorg. Med. Chem. Lett. 14 (2004) 4221–4224
4223
bromine meets the steric and electronic requirements for
this position, hence further optimization of the carba-
mate region was carried out by retaining the bromo
substituent for the C-2 position. Changing the methyl
carbamate 15 to other alkyl carbamates like ethyl, n-
propyl, propargyl, allyl, i-butyl or neopentyl carbamates
activity against a panel of human polymerases including
mitochondrial DNA polymerase gamma, and other
unrelated viral polymerases up to 80 lM, demonstrating
its specificity for the HCV polymerase. However, the
low permeability characteristic of bis carboxylic acids
rendered these compounds without significant effect in
the replicon system, but provides a novel chemotype
specific for HCV polymerase for further exploration.
(
examples 20–25) did not decrease the potency signifi-
cantly. Homologation of the acid side chain by 1 carbon
example 26) rendered the molecule inactive. Attempts
(
to remove the carbamate moiety leading the unsubsti-
tuted glycinamide resulted in inactive compound.
However, a small alkyl group like methyl can replace the
carbamate moiety and the resulting N-methylated gly-
cinamides were equipotent (examples 27 and 28). Of the
other groups experimented for the R region, an acetic
1
acid moiety was found to be more favourable than a
carbamate or methyl group as shown by example 29.
In conclusion, we have identified [(naphthalene-1-car-
bonyl)-amino]-acetic acid derivatives as a novel class of
HCV NS5B RNA dependent RNA polymerase inhibi-
tors. We have explored the structure activity require-
ment for this class of inhibitors and identified simpler
naphthyl amide bis carboxylic acid analogs as sub
micro-molar inhibitors.
The above observation prompted us to explore substi-
tuted naphthyl amides using bis carboxylic acids as part
Acknowledgements
11
of the amino acid component as shown in Table 2.
When comparing the four pairs of compounds (exam-
ples 30–37), it was very clear that using -glutamic acid
had significant improvement in potency compared to
The authors would like to thank Discovery Analytical
Chemistry group at Wyeth Research, Pearl River, NY
for spectral data.
L
L
-
aspartic acid. Also, it was interesting to see that the bis
carboxylic acid moiety seems to have a better impact on
the inhibitory effect than the aromatic substituents itself.
Although the trend we observed in the carbamate series
was noticed in these analogs as well, simpler disubsti-
tuted analogs like 35 and 37 also displayed sub micro-
molar potency. However, the bromo group seems to be
the ideal group for the C-2 position in this series as well
and an electron releasing methoxy group was undesir-
able.
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1
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2
50
ranging from 0.12–1.8 lM. It showed no inhibitory
3
4
Table 2. HCV NS5B inhibitory activity of naphthyl amide bis car-
boxylic acid derivatives
Example
R
2
R
5
R
6
n
IC50
10
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(lM)
30
31
32
33
34
35
36
37
38
Br
Br
F
CF
CF
CF
CF
Br
3
3
3
3
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
1
2
1
2
1
2
1
2
1
0.91
0.12
2.1
F
1.4
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H
1.2
0
6
. Inhibition of Hepatitis C Virus RNA Replication by 2 -
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H
Br
0.59
1.3
H
CF
CF
H
3
H
OMe
3
0.49
>10