1642
M. Pal et al. / Bioorg. Med. Chem. Lett. 13 (2003) 1639–1643
hydroxyl group (2 and 7, Table 1). Interestingly, com-
plete loss of activity was observed in the case of corre-
sponding methylsulfinyl or methylsulfonyl analogue (3
and 4, Table 1). Based on their IC50 compound 5 and 8
was identified as potent COX-2inhibitor (IC 50 ꢁ0.5–0.6
mM) with good selectivity (COX-1: IC50 >30–45 mM).
Acknowledgements
The authors would like to thank Dr. A. Venkateswarlu,
Dr. R. Rajagopalan and Prof. J. Iqbal for their constant
encouragement and the Analytical Department for spec-
tral support. MP also thanks DRL for allowing him to
attend the XVIIth International Symposium on Medic-
inal Chemistry, September 1–5, 2002, Barcelona, Spain.
Structure–activity studies for the diaryl heterocyclic
class of selective COX-2inhibitors have shown that
both methylsulfonyl and aminosulfonyl, which can dis-
pose a pair of oxygen atoms, are well recognized to be
References and Notes
17
important moieties for optimal COX-2inhibition.
Removal of oxygen essentially altered the selectivity for
1. Gans, K. R.; Galbraith, W. K.; Roman, R. J.; Haber, S. B.;
Kerr, J. S.; Schmidt, W. K.; Smith, C.; Hewes, W. E.; AcKer-
man, N. R. J. Pharmacol. Exp. Ther. 1990, 254, 180.
18
COX-2inhibition. This phenomenon was also seen in
our naphthafuranone derivatives 1 and 6 as shown in
Table 1. However, the reason for the moderate selectiv-
ity shown by their hydroxyl analogues 2 and 7 is not
clear at present. Among the methanesulfone derivatives
the reason for inactivity of compound 4 is also unclear.
Lack of required conformation for COX-2inhibition
seemed to be lost in such case. On the other hand, pre-
sence of hydrophilic hydroxy group clearly disfavored
the cyclooxygenase inhibitory activities in terms of
selectivity as well as potency (4 vs 5, Table 1) keeping
the methylsulfonyl moiety intact. Nevertheless, com-
pounds 5 and 8 which possess an additional ring that
provide them a restricted conformational freedom
showed good COX-2inhibitory activity suggesting that
they possess the required conformation for inhibiting
COX-2. In order to gain further knowledge on the role
of restricted conformation in COX-2potency as well as
selectivity in the present case freely rotating analogue
(i.e., without fused cyclohexyl ring but with an alkyl
group) of COX-2inhibitor 5, that is 5-ethyl-3-(4-
methylsulfonylphenyl)-4-phenyl-2,5-dihydro-2-furanone
(17) was synthesized19 and tested in vitro. The di-
arylfuranone 17 was found to be less active than 5 in
both the inhibition (COX-1: 20% inhibition @ 100 mM;
COX-2: 14% inhibition @ 100 mM) confirming the
restricted conformational freedom as an essential
requirement for the inhibition of both the isoforms
especially COX-2in the case of methanesulfonyl deri-
vatives. Their hydroxyl analogue, for example 4, how-
ever, clearly shows deviation from this observed
phenomenon.
2. Futaki, N.; Takahashi, S.; Yokoyama, M.; Arai, I.; Higu-
chi, S.; Otomo, S. Prostaglandins 1994, 47, 55.
3. (a) Simon, L. S.; Lanza, F. L.; Lipsky, P. E.; Hubbard,
R. C.; Talwalker, S.; Schwart, B. D.; Isakson, P. C.; Geis, G. S.
Arthritis Rheum. 1998, 41, 1591. (b) Penning, T. D.; Talley,
J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Doctor,
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.;
Berton, E. G.; Cogburn, J. N.; Gregory, S. A.; Kobolt, C. M.;
Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Iaskson, P. C. J. Med. Chem. 1997, 40, 1347.
4. (a) Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charl-
son, S.; Cromlish, W.; Ether, D.; Evans, J. F.; Ford-Hutch-
inson, A. W.; Gauthier, J. Y.; Gordon, R.; Guay, J.; Gresser,
M.; Kargman, S.; Kennedy, B.; Leblanc, Y.; Leger, S.; Man-
cini, J.; O’Neil, G. P.; Ouellet, M.; Percival, M. D.; Perrier, H.;
Riendeau, D.; Rodger, I.; Tagari, P.; Therien, M.; Vickers, P.;
Wong, E.; Xu, L.-J.; Young, R. N.; Zamboni, R.; Boyce, S.;
Rupniak, N.; Forrest, M.; Visco, D.; Patrick, D. Bioorg. Med.
Chem. Lett. 1999, 9, 1773. (b) Chan, C.-C.; Boyce, S.; Brideau,
C.; Charlson, S.; Cromlish, W.; Ethier, D.; Evans, J.; Ford-
Hutchinson, A. W.; Forrest, M. J.; Gauthier, J. Y.; Gordon,
R.; Gresser, M.; Guay, J.; Kargman, S.; Kennedy, B.;
Leblanc, Y.; Leger, S.; Mancini, J.; O’Neil, G. P.; Ouellet, M.;
Patrick, D.; Percival, M. D.; Perrier, H.; Prasit, P.; Rodger, I.;
Tagari, P.; Therien, M.; Vickers, P.; Visco, D.; Wang, Z.;
Webb, J.; Womg, E.; Xu, L.-J.; Young, R. N.; Zambani, R.;
Riendeau, D. J. Pharmacol. Exp. Ther. 1999, 290, 551.
5. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.;
Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Rogers,
R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert, K.
J. Med. Chem. 2000, 43, 775.
6. Friesen, R. W.; Brideau, C.; Chan, C. C.; Charleson, S.;
Deschenes, D.; Dube, D.; Ethier, D.; Fortin, R.; Gauthier,
J. Y.; Girard, Y.; Gordon, R.; Greig, G. M.; Riendeau, D.;
Savoie, C.; Wang, Z.; Wong, E.; Visco, D.; Xu, L. J.; Young,
R. N. Bioorg. Med. Chem. Lett. 1998, 8, 2777.
Conclusion
7. Riendeau, D.; Percival, M. D.; Boyce, S.; Brideau, C.;
Charlson, S.; Cromlish, W.; Ethier, D.; Evans, J.; Falgueyret,
J.-P.; Ford-Hutchinson, A. W.; Gordon, R.; Greig, G.; Gres-
ser, M.; Guay, J.; Kargman, S.; Leger, S.; Mancini, J. A.;
O’Neil, G.; Ouellet, M.; Rodger, I. W.; Therien, M.; Wang, Z.;
Webb, J. K.; Wong, E.; Xu, L.; Young, R. N.; Zamboni, R.;
Prasit, P.; Chan, C.-C. B. J. Pharmacol. 1997, 121, 105.
8. (a) Li, C.-S.; Black, W. C.; Brideau, C.; Chan, C.-C.;
Charlson, S.; Cromlish, W. A.; Claveau, D.; Gauthier, J. Y.;
Gordon, R.; Greig, G.; Grimm, E.; Guay, J.; Lau, C. K.;
Riendeau, D.; Therien, M.; Visco, M. D.; Wong, E.; Xu, L.;
Prasit, P. Bioorg. Med. Chem. Lett. 1999, 9, 3181. (b) Leblanc,
Y.; Roy, P.; Boyce, S.; Brideau, C.; Chan, C.-C.; Charlson, S.;
Gordon, R.; Grimm, E.; Guay, J.; Leger, S.; Li, C. S.; Rien-
deau, D.; Visco, D.; Wang, Z.; Webb, J.; Xu, L. J.; Prasit, P.
Bioorg. Med. Chem. Lett. 1999, 9, 2207.
In conclusion we have described synthesis and cyclo-
oxygenase inhibiting properties of a number of 1-aryl
substituted naphthofuranones having methylsulfanyl,
methylsulfinyl or methanesulfone moiety attached to the
p-position of the aryl ring. Initial SAR studies indicate
that restricted conformation along with the presence of
methanesulfone moiety is crucial for optimal COX-2
inhibition in this series, whereas methylsulfanyl deriva-
tives having a hydroxyl group show moderate selectivity
in COX-2inhibition over COX-1. Some of the com-
pounds synthesized are potent and selective COX-2
inhibitors in vitro and therefore provide a useful basis
for the development of a novel anti-inflammatory agent
without having the side effects of non-selective NSAIDs.