4486
L. Navidpour et al. / Bioorg. Med. Chem. Lett. 16 (2006) 4483–4487
´
Therien, M.; Vickers, P.; Wong, E.; Xu, L.-J.; Young, R.
parecoxib (63% and 42% reduction in inflammation at 3
and 5 h postdrug administration, respectively), adminis-
tered at the same dose.
N.; Zamboni, R. Bioorg. Med. Chem. Lett. 1999, 9, 1773.
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.
10. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.;
Koboldt, C. M.; Massferrer, 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.
To establish their GI safety profile, these compounds
were evaluated in the acute gastric toxicity study.26
Intravenous administration of 20 mg/kg of diclofenac
sodium produced marked, visible, hemorrhagic gastric
lesions with more petechiae 4 h after its administration.
In contrast, compounds 9 and 13 were without any effect
at a high dose (20 mg/kg, iv) as shown in Table 1.
11. Riendeau, D.; Percival, M. D.; Brideau, C.; Charleson, S.;
´
As indicated above, an adequate aqueous solubility was
of critical importance in order to develop an intravenous
dosage form. The in situ preparation of the potassium
salt (by adding 1 equiv of KOH) provided a solubility
of 125 and 100 mg/mL in water for compounds 9 and
13, respectively.4,27
Dube, D.; Ethier, D.; Falgueyret, J. P.; Friesen, R. W.;
Gordon, R.; Greig, G.; Guay, J.; Mancini, J.; quelled, M.;
Wong, E.; Xu, L.; Boyce, S.; Visco, D.; Girard, Y.; Prasit,
P.; Zamboni, R.; Rodger, I. W.; Gresser, M.; Ford-
Hutchinson, A. W.; Young, R. N.; Chan, C. C.
J. Pharmacol. Exp. Ther. 2001, 296, 558.
´
12. Dogne, J. M.; Supuran, C. T.; Pratico, D. J. J. Med.
Chem. 2005, 48, 2251.
13. Grosser, T.; Fries, S.; FitzGerald, G. A. J. Clin. Invest.
2006, 116, 4.
14. Talley, J. J.; Bertenshaw, S. R.; Brown, D. L.; Carter, J. S.;
Graneto, M. J.; Kellogg, M. S.; Koboldt, C. M.; Yuan, J.;
Zhang, Y. Y.; Seibert, K. J. Med. Chem. 2000, 43, 1661.
15. Habeeb, A. G.; Praveen Rao, P. N.; Knaus, E. E. J. Med.
Chem. 2001, 44, 3039.
16. Navidpour, L.; Shafaroodi, H.; Abdi, K.; Amini, M.;
Ghahremani, M. H.; Dehpour, A. R.; Shafiee, A. Bioorg.
Med. Chem. 2006, 14, 2507.
17. Therin, M.; Gauthier, J. Y.; Leblanc, Y.; Leger, S.;
Perrier, H.; Prasit, P.; Wang, Z. Synthesis 2001, 12, 1778.
18. Shie, J.-J.; Fang, J.-M. J. Org. Chem. 2003, 68, 1158.
19. Spectral data for compounds 8, 9, 12 and 13. 4-(4-
Cyanophenyl)-3-phenyl-2(5H)-furanone (8). Yield 45%.
The results of this investigation show that: (i) rofecoxib
(9) and celecoxib (13) analogues, having a tetrazole ring
in place of the respective SO2Me and SO2NH2 pharma-
cophores provide potent and selective inhibition of the
COX-2 isozyme, (ii) molecular modeling studies indicate
the tetrazole ring inserts deep into the COX-2 secondary
pocket, forming hydrogen bonds with Arg513, His90,
Gln192, and (iii) the tetrazole ring is a suitable water-sol-
uble replacement with respect to selective COX-2 inhibi-
tion and AI activity for parenteral treatment of acute
pain.
Acknowledgments
Mp 156–158 ꢁC. IR (KBr): 2228 (CN), 1752 (CO) cmꢀ1
.
This work was supported by grants from the INSF (Iran
National Science Foundation).
1H NMR (CDCl3) d 7.65 (d, J = 8.8 Hz, 2H), 7.43 (d,
J = 8.8 Hz, 2H), 7.42–7.37 (m, 5H), 5.19 (s, 2H). MS m/z
(%) 261 (M+, 90), 232 (30), 217 (13), 204 (100), 176 (9), 131
(15). Anal. Calcd for C17H11NO2: C, 78.15; H, 4.24; N,
5.36. Found: C, 78.36; H, 4.10; N, 5.49.
References and notes
4-[4-(5-Tetrazolyl)phenyl]-3-phenyl-2(5H)-furanone (9).
Yield 60%. Mp 256–258 ꢁC. IR (KBr): 3452 (NH), 1731
1. DeWitt, D. L. Mol. Pharmacol. 1999, 55, 625.
2. Chung, S.; Lim, K. M.; Shin, S. S. Expert Opin. Ther.
Patents 2005, 15, 9.
3. Talley, J. J.. In King, F. D., Ed.; Progress in Medicinal
Chemistry; Elsevier: Amsterdam, 1999; Vol. 36, p 201.
(CO) cmꢀ1 1H NMR (DMSO-d6) d 8.03 (d, J = 8.4 Hz,
.
2H), 7.59 (d, J = 8.4 Hz, 2H), 7.47–7.42 (m, 3H), 7.40–7.37
(m, 2H), 5.43 (s, 2H). MS m/z (%) 304 (M+, 100), 292 (44),
281 (18), 273 (18), 219 (14), 204 (10), 178 (12). Anal. Calcd
for C17H12N4O2: C, 67.10; H, 3.97; N, 18.41. Found: C,
66.98; H, 3.81; N, 18.59.
´
4. Almansa, C.; Bartolı, J.; Belloc, J.; Cavalcanti, F. L.;
Ferrando, R.; Gomez, L. A.; Ramis, I.; Carceller, E.;
´
´
Merlos, M.; Garcıa-Rafanell, J. J. Med. Chem. 2004, 47,
5579.
1-(4-Cyanophenyl)-5-(4-methylphenyl)-3-(trifluoromethyl)-
1H-pyrazole (12). Yield 50%. Mp 107–109 ꢁC. IR (KBr):
2228 (CN) cmꢀ1. 1H NMR (CDCl3) d 7.65 (d, J = 8.8 Hz,
2H), 7.46 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8 Hz, 2H), 7.11
(d, J = 8 Hz, 2H), 6.74 (s, 1H), 2.78 (s, 3H). MS m/z (%)
327 (M+, 100), 313 (5), 306 (12), 292 (16), 275 (13). Anal.
Calcd for C18H12F3N3: C, 66.05; H, 3.70; N, 12.84.
Found: C, 66.22; H, 3.88; N, 12.67.
5. Kimmel, S. E.; Berlin, J. A.; Kinman, J. L.; Hennessy, S.;
Feldman, H.; Carson, J. L.; Storm, B. L. Pharmacoepi-
demiol. Drug Saf. 2002, 11, 113.
6. Xie, W.; Chipman, J. G.; Robertson, D. L.; Erikson, R.
L.; Simmons, D. L. Proc. Natl. Acad. Sci. U.S.A. 1991, 88,
2692; Jujubu, D. A.; Fletcher, B. S.; Varnum, B. C.; Lim,
R. W.; Herschman, H. R. J. Biol. Chem. 1991, 266, 12866.
7. Vane, J. R. Nature 1994, 367, 215; Masferrer, J. L.;
Zweifel, B. S.; Manning, P. T. Proc. Natl. Acad. Sci.
U.S.A. 1994, 91, 3228.
4-(4-Methylphenyl)-1-[4-(5-tetrazolyl)phenyl]-3-(trifluoro-
methyl)-1H-pyrazole (13). Yield 51%. Mp 220–222 ꢁC. IR
1
(KBr): 3420 (NH) cmꢀ1. H NMR (DMSO-d6), d 8.11 (d,
J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.38–7.08 (m,
5H), 2.32 (s, 3H). MS m/z (%) 370 (M+, 76), 341 (95), 327
(100), 321 (19), 306 (25), 292 (12), 273 (15), 258 (14). Anal.
Calcd for C18H13F3N6: C, 58.38; H, 3.54; N, 22.69.
Found: C, 58.29; H, 3.69; N, 22.82.
8. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charleson,
S.; Cromlish, W.; Ethier, 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.; Mancini, J.; ONeill, G. P.; Quellet, M.; Percival,
M. D.; Perrier, H.; Riendeau, D.; Rodger, Y.; Tagari, P.;
20. Docking studies were performed using MOE software
version 2003.02 (CCG Inc.). The coordinates of the X-ray