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Table 1. NOS-Inhibitory Activity of Compounds 1—18
Inhibition rate
Compound
X
Y
Z
R1
R2
1 mM
100 mM
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
H2
O
—
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
3Ј-Me
H
5Ј-Me
H
Ͻ10%
42Ϯ8%
66Ϯ18%
64Ϯ5%
(69Ϯ6%)a)
79Ϯ12%
61Ϯ17%
44Ϯ14%
31Ϯ17%
Ͻ10%
Ͻ10%
Ͻ10%
71Ϯ16%
74Ϯ5%
(50Ϯ3%)a)
Ͻ10%
Ͻ10%
63Ϯ10%
31Ϯ5%
26Ϯ9%
58Ϯ20%
25Ϯ2%
17Ϯ6%
Ͻ10%
2Ј-Me
2Ј-Et
2Ј-iPr
2Ј-Me
2Ј-Me
2Ј-Me
3Ј-Me
2Ј-Me
2Ј-Et
2Ј-iPr
2Ј-Et
2Ј-Et
2Ј-Et
2Ј-Et
6Ј-Me
6Ј-Et
6Ј-iPr
6Ј-Et
6Ј-iPr
5Ј-Me
5Ј-Me
6Ј-Me
6Ј-Et
6Ј-iPr
6Ј-Et
6Ј-Et
6Ј-Et
6Ј-Et
NH
NH
NH
C(OH)OMe
CF2
41Ϯ18%
42Ϯ12%
46Ϯ3%
NH
NH
Thalidomide (1)
NNA (2)
23Ϯ8%
87Ϯ7%
Ͻ10%
74Ϯ28%
a) Inhibitory activity of 7 and 17 was measured at 0.5 mM instead of 1 mM, because these compounds showed poor solubility.
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tivity, while reduction of another carbonyl group at position
1, i.e., compound 18, did not affect the activity. We cannot
interpret these phenomena at this stage.
Chemically, homophthalimide derivatives are autoxidized
at the benzylic methylene position in the tetrahydroisoquino-
line ring to give a hemiacetal analog (15) in methanol or a
tricarbonyl analog in water.12,24,25) Therefore, N-phenylho-
mophthalimides (4—11) might inhibit the production from
NO of nitrite/nitrate, which are the products measured di-
rectly by Ichimori’s protocols,22,23) through self-oxidization.
However, the inhibitory activity of non-oxidizable analogs,
i.e., the hemiacetal analog (15: already oxidized) and difluo-
rinated analog (16: blocked at the benzylic position) is al-
most the same as that of the corresponding homophthalimide
compound 6. This result suggests that N-phenylhomophthal-
imides (4—11) inhibit NOS directly, but do not merely in-
hibit production of nitrite/nitrate from NO.
In conclusion, we found firstly that thalidomide (1) has
NOS-inhibitory activity, even though the activity is weak,
and secondly, that some N-phenylhomophthalimide deriva-
tives possess NOS-inhibitory activity which is more potent
than that of thalidomide. Although the structure–activity re-
lationships remain to be investigated, and the structure has
not been optimized yet, the prepared compounds show mod-
erate activity and represent a new class of non-amino-acid-
based NOS inhibitors. Further structural development aiming
at improvement of the NOS-inhibiting activity and at NOS
isoform selectivity is in progress.
Acknowledgment The work described in this paper was partially sup-
ported by Grants-in-Aid for Scientific Research from The Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan.
References and Notes
1) Present address: Pharmaceuticals and Medical Devices Evaluation
Center, National Institute of Health Sciences; Toranomon 33rd Mori
Bldg., 3–8–21 Toranomon, Minato-ku, Tokyo 105–8409 Japan.
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