M. Sharma, S. M. Ray / Bioorg. Med. Chem. Lett. 17 (2007) 6790–6796
Table 7. Study with Cytochrome P450 enzyme inhibitor
6795
Compound
Increase in paw volume (ml) SEM (% inhibition of edema)
1 h
2 h
3 h
4 h
6 h
24 h
SKF-525A & 7c
0.075 0.0138
[64.29]
0.18 0.0151
[56.10]
0.26 0.0183
[56.67]
0.24 0.0169
[57.89]
0.19 0.0135
[59.57]
0.07 0.0114
[68.18]
7c
0.07 0.0147
[66.7]
0.21 0.0267
0.17 0.0176
[58.53]
0.41 0.0148
0.24 0.0154
[60.0]
0.60 0.0173
0.23 0.0143
[59.65]
0.57 0.0203
0.185 0.0161
[60.63]
0.47 0.0165
0.07 0.0125
[68.18]
0.22 0.0135
Control
Male Wistar rats were pretreated with SKF 525A (50 mg/kg i.p.) and one hour later, test drug 7c was administered at 100 mg/kg p.o.
The remaining protocol followed was the same as that of anti-inflammatory screening by carrageenan induced rat paw edema model.
Each value represents means SEM (n = 6).
The results obtained were analyzed by Student’s t-test and the difference between the two groups was not found to be statistically significant.
Tamas, T.; Toth, G.; Zagyva, A.; Zekany, A.; Lavian, G.;
Gross, A.; Friedman, R.; Razin, M.; Huang, W.; Krais,
B.; Chorev, M.; Youdim, M. B.; Weinstock, M. J. Med.
Chem. 2002, 45, 5260.
cant antipyretic activity in LPS induced pyresis. The
adjuvant induced arthritis study reveals that these com-
pounds though have longer activity profile are not effec-
tive in preventing the formation of secondary lesions.
The compounds were found to be free from ulcerogenic-
ity liability of common NSAIDs. Further evaluation of
COX-2 inhibition is required for establishing the mech-
anism of their low gastrointestinal toxicity.
13. Juby, P. F.; Goodwin, W. R.; Hudyma, T. W.; Partyka, R.
A. J. Med. Chem. 1972, 15, 1297.
14. Ray, S. M.; Lahiri, S. C. J. Ind. Chem. Soc. 1990, 67, 324.
15. Aono, T.; Kishimoto, S.; Araki, Y.; Noguchi, S. Chem.
Pharm. Bull. 1977, 25, 3198.
16. Noguchi, S.; Kishimoto, S.; Minamida, I.; Obayashi, M.;
Kawakita, K. Chem. Pharm. Bull. 1971, 19, 646.
17. Wiesenberg-Boettcher, I.; Schweizer, A.; Muller, K.
Agents Actions 1989, 26, 240.
Acknowledgments
18. Kalgutkar, A. S.; Crews, B. C.; Rowlinson, S. W.;
Marnett, A. B.; Kozak, K. R.; Remmel, R. P.; Marnett,
L. J. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 925.
19. Kalgutkar, A. S.; Marnet, A. B.; Crews, C. B.; Remmel,
R. P.; Marnett, L. S. J. Med. Chem. 2000, 43, 2860.
20. Kalgutkar, A. S.; Rowlinson, S. W.; Crews, B. C.;
Marnett, L. J. Bioorg. Med. Chem. Lett. 2002, 12, 521.
21. Zovko, M.; Zorc, B.; Takac, M. J.; Metelko, B.; Novak, P.
CCACAA 2003, 76, 335.
We are grateful to the Birla Institute of Technology and
Science, Pilani, for financial support and laboratory
facility for this work and to the University Grants Com-
mission (UGC), New Delhi, for providing a Junior Re-
search Fellowship to M. Sharma.
References and notes
22. Vogel’s Textbook of Practical Organic Chemistry, Fur-
niss, B.S.; Hannaford, A.J.; Smith, P.W.G.; Tatchell, A.R.
Eds; Pearson Education; 2004; p 987.
23. Lahiri, S. C.; Gupta, J. K. J. Indian Chem. Soc. 1976, LIII,
1040.
1. Ganellin, C. R. In Advances in Drug Research; Harper, N.
J., Simmonds, A. B., Eds.; Academic Press: London, 1967;
Vol. 4, pp 163–249.
2. Woltersclorf, O. W., Jr.; Desolms, S. J.; Cragoe, E. J., Jr.
J. Med. Chem. 1981, 24, 874.
24. Balsamo, A.; Barili, P. L.; Crotti, P.; Macchia, F.; Pecchia,
A.; Cuttica, A.; Passerini, N. J. Med. Chem. 1975, 18, 842.
25. Synthesis of diethyl 2,4-diacetyl-3-(3,4-dimethoxy-
phenyl)pentanedionate (3): Veratraldehyde (2) (34 g,
0.2 mol) was dissolved in ethylacetoacetate (60 g,
0.43 mol) in a dry conical flask and piperidine (2.5 ml)
was added at ambient temperature and then kept for 3
days or more (up to seven days, depending on room
temperature) with the mouth stoppered. The solid product
thus obtained was crushed and then washed with solvent
ether to get the product in 70–75% yield. Recrystallization
from dil. alcohol gave the analytical product. Mp 129–
131 °C, IR (cmꢀ1): 1720(C@O stretching), 1145 (OCH3),
1H NMR: d (ppm) (CDCl3):1.28 (t, CH3, 6H), 2.10 (s,
CH3, 6H), 3.02 (d, CH, H), 3.63 (d, CH, H), 3.85 (s,
OCH3, 3H), 3.87 (s, OCH3, 3H), 3.93 (qr, CH2, 4H), 4.18
(t, CH, 1H), 6.64 (s, ArH, H), 6.73 (s, ArH, 2H).
26. Synthesis of 3,4-dimethoxyphenylpentanedioic acid (4):
Compound 3 (40 g, 0.089 mol) was dissolved in a hot
solution of KOH (160 g in 120 ml of water) and 80 ml of
90% ethanol was added. The hot reaction mixture was
refluxed on a water bath for 1 h. Alcohol was then
removed as far as possible by distillation under reduced
pressure, and after dilution with water it was cooled and
washed with solvent ether. The aqueous layer on acidifi-
cation with cold conc. HCl with cooling gave crude 4
3. Lahiri, S. C.; De, N. C. J. Med. Chem. 1968, 11, 900.
4. Ray, S. M.; Lahiri, S. C. J. Indian Chem. Soc. 1991, 68, 549.
5. Karaguni, I. M.; Glusenkamp, K. H.; Langerak, A.;
Geisen, C.; Ullrich, V.; Winde, G.; Moroy, T.; Muller, O.
Bioorg. Med. Chem. Lett. 2002, 12, 709.
6. Chairini, A.; Ferranti, A.; Giovanninetti, G.; Matteuzzi,
D. Farmaco[Sci.] 1980, 35, 413.
7. Sheng, R.; Lin, X.; Li, J.; Jiang, Y.; Shang, Z.; Hu, Y.
Bioorg. Med. Chem. Lett. 2005, 15, 3834.
8. Molteni, V.; Rhodes, D.; Rubins, K.; Hansen, M.;
Bushman, F. D.; Siegel, J. S. J. Med. Chem. 2000, 43,
2031.
9. Hall, I. H.; Wong, O. T.; Chi, L. K.; Chen, S. Y.
Anticancer Res. 1994, 14, 2053.
10. Mignani, S.; Bohme, G. A.; Birraux, G.; Boireau, A.;
Jimonet, P.; Damour, D.; Genevois-Borella, A.; Debono,
M-W.; Pratt, J.; Vuilhorgne, M., et al. Bioorg. Med.
Chem. 2002, 10, 1627.
11. Musso, D. L.; Cochran, F. R.; Kelley, J. L.; McLean, E.
W.; Selph, J. L.; Rigdon, G. C.; Orr, G. F.; Davis, R. G.;
Cooper, B. R.; Styles, V. L.; Thompson, J. B.; Hall, W. R.
J. Med. Chem. 2003, 46, 399.
12. Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, N.; Lerner,
D.; Goldenberg, W.; Miskolczi, I.; Molnar, S.; Rantal, F.;