J. Bosch et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1745±1748
1747
Table 1. In vitro COX-1 and COX-2 enzyme data for substituted 1,3,4-triaryl-3-pyrrolin-2-ones 1
Compound
R
1
R
2
R
3
R
4
R
5
COX-2a
COX-1a
Selectivity
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
H
F
H
H
Cl
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
F
CH
CF
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
0.28Æ0.09
0.90Æ0.14
1.00Æ0.12
0.35Æ0.14
1.00Æ0.09
0.98Æ0.21
0.34Æ0.09
0.31Æ0.12
0.32Æ0.14
0.22Æ0.05
1.05Æ0.25
0.28Æ0.10
1.05Æ0.12
1.20Æ0.41
0.95Æ0.63
0.30Æ0.14
1.00Æ0.21
0.53Æ0.18
0.41Æ0.07
2.40Æ0.60
10.80Æ1.96
9.80Æ0.90
5.86Æ0.08
6.90Æ1.10
5.10Æ1.20
2.68Æ0.85
2.70Æ0.61
2.50Æ0.48
2.30Æ0.90
4.00Æ1.05
2.50Æ0.65
3.70Æ0.59
5.28Æ0.94
7.20Æ1.10
2.50Æ0.39
8.20Æ1.60
9.73Æ2.02
0.19Æ0.06
8.6
12.0
9.8
16.7
6.9
5.2
7.9
8.7
7.8
10.5
3.8
8.9
3.5
4.4
7.6
8.3
8.2
H
H
H
H
H
H
F
Cl
3
CH O
H
H
H
H
H
H
3
3
CH
3
O
F
F
CH
F
3
O
CH
F
3
O
CH
3
CH
CF
F
3
O
F
F
3
CH
F
3
O
H
Celecoxib
Indomethacin
18.4
0.5
aIC50 (mM). Average of 2±4 determinations. PGE2 levels in lipopolysaccharide (LPS)-challenged human whole blood and tromboxane 2 (TxB2)
levels following blood coagulation were measured as biochemical index for COX-2 and COX-1, respectively (see ref 14).
COX inhibitor indomethacin are included for the purpose
of a clear SAR summary. As can be seen in the Table,
the in vitro COX-2 potency of both the parent lactam 1a
and other substituted lactams bearing a F atom at the para
position of either the N- or 3-phenyl ring (1d and 1h,
respectively) or a para methoxy 3-phenyl substituent (1g)
is higher than that of celecoxib. This good COX-2
potency is maintained when there are additional halogen
2. (a) Laneuville, O. J. Pharmacol. Exp. Ther. 1994, 271, 927.
b) Masferrer, J. L.; Zweifel, B. S.; Manning, P. T.; Hauser, S.
D.; Leahy, K. M.; Smith, W. G.; Isakson, P. C.; Seibert, K.
(
Proc. Natl. Acad. Sci. USA 1994, 91, 3228.
3
. (a) Pirson, Y.; Van Ypersele de Strihou, C. Am. J. Kidney Dis.
986, 8, 337. (b) Allison, M. C.; Howatson, A. G.; Torrance, C.
1
J.; Lee, F. D.; Russell, R. I. G. N. Engl. J. Med. 1992, 327, 749.
. Stewart, W. F.; Kawas, M.; Corrada, M.; Metter, E. J.
Neurology 1997, 48, 626.
4
(
1
F or Cl) substituents in the N-phenyl ring (1i, 1j, 1l or
p), but strongly decreases with the introduction of
bulkier ortho or para substituents (CH , CF or CH O).
5. Prescott, S. M.; White, R. L. Cell 1996, 87, 783.
6. For a review on selective inhibitors of COX-2 see: (a)
Beuck, M. Angew. Chem., Int. Engl. Ed. 1999, 38, 631. (b)
Carter, J. S. Expert. Opin. Ther. Pat. 1998, 8, 21. (c) Prasit, P.;
Riendeau, D. Ann. Rep. Med. Chem. 1997, 32, 211. (d) Talley,
J. J. Expert. Opin. Ther. Pat. 1997, 7, 55. (e) Chan, C. C.;
Rodger, I. W. Adv. Exp. Med. Biol. 1996, 407, 157.
3
3
3
As far as the selectivity ratio COX-1/COX-2 is concerned,
most of the lactams 1 proved to be selective COX-2 inhi-
bitors. The best ratios were obtained with lactams 1b and,
especially, 1d, which bear a ¯uorine atom at the 2- or 4-
position, respectively, of the N-phenyl ring. An additional
substitution on this ring or at the 3- or 4-position of the 3-
phenyl ring does not improve the selectivity.
7
. Futaki, N.; Takahashi, S.; Yokoyama, M.; Arai, I.; Higuchi,
S.; Otomo, S. Prostaglandins 1994, 47, 55.
. Ducharme, Y.; Gauthier, J. Y.; Prasit, P.; Leblanc, Y.;
8
Wang, Z.; Leger, S.; Therien, M. WO Patent 9518799, 1995;
Chem Abstr. 1996, 124, 201998.
In summary, we have designed and synthesized a variety
of novel 1,3,4-triaryl-3-pyrrolin-2-ones 1 as selective
COX-2 inhibitors. These compounds, in particular 1b and
9. Penning, T. D.; Talley, J. J.; Bertenshaw, S. R.; Carter, J. S.;
Collins, P. W.; Docter, S.; Graneto, M. J.; Lee, L. F.; Malecha, J.
W.; Miyashiro, J. M.; Rogers, R. S.; Rogier, D. J.; Yu, S. S.;
Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.;
Zhang, Y. Y.; Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
1
5
1d, may represent a new generation of NSAIDs, useful
for symptomatic treatment of in¯ammatory diseases such
as rheumatoid arthritis or osteoarthritis.
1
0. Weiner, S. J.; Kollman, P. A.; Case, D. A.; Singh, U. C.;
Ghio, C.; Alagona, G.; Profeta, S. Jr.; Weiner, P. J. Am.
Chem. Soc. 1984, 106, 765.
Acknowledgements
1
1. (a) Wong, E.; Bayly, C.; Watermann, H. L.; Riendeau, D.;
Mancini J. A. J. Biol. Chem. 1997, 272, 9280. (b) Greig, G. M.;
Donna, A. F.; Falgueyret, J.-P.; Ouellet, M.; Percival, M. D.;
Roy, P.; Boily, C.; Mancini, J. A.; O'Neill, G. P. Mol. Pharm.
This work was supported in part by the CICYT (Spain)-
European Comission (project 2FD97-0450). Thanks are
also due to the Comissionat per Universitats i Recerca
1
997, 52, 829. (c) Mancini, J. A.; Vickers, P. J.; O'Neill, G. P.;
Boily, C.; Falgueyret, J.-P.; Rindeau, D. Mol. Pharm. 1997,
1, 52. (d) So, O.-Y.; Scara®a, L. E.; Mak, A. Y.; Callan, O.
(
Generalitat de Catalunya) for Grant 1999SGR-00079.
5
H.; Swinney, D. C. J. Biol. Chem. 1998, 273, 5801. (e) Rieke,
C. J.; Mulichak, A. N.; Garavito, R. M.; Smith, W. L. J. Biol.
Chem. 1999, 274, 17109.
References and Notes
1
. (a) O'Banion, M. K.; Sadowski, H. B.; Winn, V.; Young,
12. Goodford, P. J. J. Med. Chem. 1985, 28, 849.
D. A. J. Biol Chem. 1991, 266, 23261. (b) Sirois, J.; Richards,
J. S. J. Biol. Chem. 1992, 267, 6382. (c) Kujubu, D. A.;
Herschmann, H. R. J. Biol. Chem. 1992, 267, 7991.
13. Huang, H.-C.; Li, J. J.; Garland, D. J.; Chamberlain, T.
S.; Reinhard, E. J.; Manning, R. E.; Seibert, K.; Koboldt, C.
M.; Gregory, S. A.; Anderson, G. D.; Veenhuizen, A. W.;