2690
J. Feixas et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2687–2690
Table 2. In vitro and in vivo results of benzyl-monosubstituted naphthalenes
Compound
R3
COX-2a
COX-1a
Selectivity
Carrageenanb
% inhib (mg/kg)
5
6
15
16
17
18
19
20
21
22
23
4-Cl
4-F
3-Cl
2-Cl
H
4-Me
4-Et
4-t-Bu
4-Ac
4-MeO
4-EtO
—
0.52Æ0.32
0.74Æ0.34
14.70Æ1.26
1.70Æ0.38
0.39Æ0.05
0.22Æ0.04
1.03Æ0.01
7.50Æ1.23
6.60Æ4.15
0.33Æ0.12
1.70Æ0.53
1.10Æ0.20
0.76Æ0.33
4.10Æ2.16
1.70Æ0.57
N.D.
2.30Æ0.06
1.50Æ0.45
2.80Æ2.13
>100
7.9
2.3
—
1.4
3.8
12.7
>97
5.4
33.0
26.6
>59.0
12.9
15.0
35 (3)*, 50 (30)*
35 (3)*, 53 (30)*
0 (3), 0 (30)
5 (3), 13 (30)
30 (3)*, 58 (30)*
30 (3)*, 49 (30)*
32 (30)*
IN (3), 32 (30)*
IN (3), IN (30)
22 (3), 45 (30)*
27 (3)*, 52 (30)*
41 (3)*, 40 (30)*
41 (3)*, 34 (30)*
40.8Æ4.30
218Æ6
8.80Æ2.05
>100
Celecoxib
Rofecoxib
14.2Æ4.40
—
11.4Æ0.81
*p<0.05.
aData are indicated as IC50 (mM)ÆSEM (n=3).
b6–7 animals per group.
References and Notes
potency, particularly at COX-1, which resulted in a
selectivity of around 100-fold.Unfortunately, this
interesting result did not translate into good in vivo
activity, producing only a 32% inhibition at 30 mg/kg in
the carrageenan model.
1.(a) Kalgutkar, A.S. Exp. Opin. Ther. Patents 1999, 9, 7.(b)
Jimenez, J. M.; Crespo, M. I.; Godessart, N. IDrugs 2000, 3,
907.
2. Black, W. C.; Bayly, C.; Belley, M.; Chan, C. C.; Charle-
son, S.; Denis, D.; Gauthier, J. Y.; Gordon, R.; Guay, D.;
Dargman, S.; Lau, C. K.; Leblanc, Y.; Mancini, J.; Ouellet, M.;
Percival, D.; Roy, P.; Skorey, K.; Tagari, P.; Vickers, P.; Wong,
E.; Xu, L.; Prasit, P. Bioorg. Med. Chem. Lett. 1996, 6, 725.
3. Puig, C.; Crespo, M. I.; Godessart, N.; Feixas, J.; Ibarzo,
J.; Jimenez, J. M.; Soca, L.; Cardelus, I.; Heredia, A.; Mir-
alpeix, M.; Puig, J.; Beleta, J.; Huerta, J. M.; Lopez, M.;
Segarra, V.; Ryder, H.; Palacios, J. M. J. Med. Chem. 2000,
43, 214.
The effect of 4-acetyl substitution (21) was loss of
activity at COX-2, whereas 4-MeO substitution (22)
produced good inhibition at this enzyme, giving rise to a
26-fold selectivity.This ratio could be increased to >59-
fold with the homologous 4-ethoxy substitution but
with some loss of COX-2 activity.It can be deduced
from these examples that selectivity can be profoundly
affected by substitution at the para position of the ben-
zyl ring and that the more potent and selective struc-
tures come from smallish groups such as methyl and
methoxy, giving rise to very active and selective mole-
cules which elicit promising in vivo activity.
4. Patrignani, P.; Panara, M. R.; Greco, A.; Fusco, O.;
Natoli, C.; Iacobelli, S.; Chipollone, F.; Ganci, A.; Creminon,
C.; Maclouf, J.; Patrono, C. J. Pharmacol. Exp. Ther. 1994,
271, 1705.
5. Brooks, P.; Emery, P.; Evans, J. F.; Fenner, H.; Hawkey,
C. J.; Patrono, C.; Smolen, J.; Breedveld, F.; Day, R.; Dou-
gados, M.; Ehrich, E. W.; Gijon-Banos, J.; Kvien, T. K.; Van
Rijswijk, M. H.; Warner, T.; Zeidler, H. Rheumatology 1999,
38, 779.
6. Miralpeix, M.; Camacho, M.; Lopez-Belmonte, J.; Cana-
lıas, F.; Beleta, J.; Palacios, J. M.; Vila, L. Br. J. Pharmacol.
1997, 121, 171.
In conclusion, we have identified a new series of selec-
tive COX-2 inhibitors that are active in an acute in vivo
model of inflammation.We have also gained an insight
into the structure–activity relationships that will allow us
to improve the properties of the series in the future.Fur-
ther work is underway and will be reported in due course.