YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Synthesis and Screening of Cyclooxygenase Activity of Hydantoin and 2-Thiohydantoin Derivatives

Hydantoin 및 2-Thiohydantoin 유도체의 합성과 사이클로옥시게나제 활성 검색

  • 신혜순 (덕성여자대학교 약학대학) ;
  • 최희전 (덕성여자대학교 약학대학) ;
  • 권순경 (덕성여자대학교 약학대학)
  • Published : 2004.04.01
Download PDF
⟨ Previous Next ⟩

Abstract

Selective COX-2 inhibitors were expected to retain anti-inflammatory activity by inhibition of prostaglandin production with reduction of gastric and renal side effect associated with non-steroidal anti-inflammatory drugs. This study reported the syntheses of novel 2-thiohydantoin and hydantoin derivatives which have the structure of 5-membered heterocyclic ring substituted with two aryl groups, phenyl group at 5-position and p-sulfamylphenyl or p-methoxyphenyl group at 1-position. These synthetic compounds showed significant COX-2 activities in vitro screening. Among them, 5-phenyl-2-thiohydantoin and hydantoin substituted with benzyl group at 3-position, compounds 5 and 8, could be considered as lead compounds with $IC_{50}$/=13.13∼18.78 $\mu\textrm{g}$/$m\ell$ for the development of COX-2 inhibitors.

Keywords

References

  1. Vane, J. R. : Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature(New Biol.) 231, 232 (1971)
  2. Dubois, R. N., Abramson, S. B., Crofford, L.,Gupta, R. A., Simon, L. S., Van de Putte, L. B. A. and Lipsky, P. E. : Cyclooxygenase in biology and disease. FASEB J. 12, 1063 (1998)
  3. Smith, W. L., Garavito, R. M. and DeWitt, D. L. : Prostaglandin endoperoxide H synthases (cyclooxygenase)-1 and -2. J. Biol. Chem. 271, 33157 (1996) https://doi.org/10.1074/jbc.271.52.33157
  4. Herschman, H. R. : Prostaglandin synthase 2. Biochim. Biophys. Acta 1299, 125 (1996)
  5. Chang, H. and Jahang, Y. : Selective cyclooxygenase-2 inhibitors as anti-inflammatory agents. Kor. J. Med. Chem. 8, 48 (1998)
  6. Michell, J. A., Akarasereenont, P., Thiemermann, C., Flower, R. J. and Vane, J. R. : Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc. Natl. Acad. Sci. USA 90 , 11693 (1994) https://doi.org/10.1073/pnas.90.24.11693
  7. Allison, M. C., Howatson, A. G., Torrance, C. J., Lee, F. D. and Russell, R. G. : Gastrointestinal damage associated with the use of non-steroidal atiinflammatory drugs. N. Engl. J. Med. 327, 749 (1992)
  8. Clive, D. M. and Stoff, J. S. : Renal syndromes associated with nonsteroidal antiinflammatory drugs. N. Engl. J. Med. 310, 563 (1984)
  9. Gans, K. R., Galbraith, W., Roman, R. J., Harber S. B., Kerr, J. S., Schmidt, W. K., Smith, C., Hewes, W. E. and Ackerman, N. R. : Antiinflammatory and safety profile of DuP 697, a novel orally effective prostaglandin synthesis inhibitor. J. Phaemacol. Exp. Ther. 54, 180 (1990)
  10. Futaki, N., Yoshikawa, K., Hamasaka, Y., Arai, I., Higuchi, S., lizuka, H. and Otomo, S. : NS-398, A novel non-steroidal antiinflammatory drug with potent analgesic and antipyretic effects, which causes minimal stomach lesions. Gen. Pharmacol. 24, 105 (1993)
  11. Penning, T. D., Talley, J. J. and Bertenshaw, S. R. et al. : Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 ingibitors: Identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib). J. Med. Chem. 40, 1347 (1997).
  12. 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., Zeifel B. S. and Seibert, K. : 4-[5-Methy1-3-phenylisoxazol-4-yl]benzenesulfonamide, Valdecoxib: A potent and selective inhibitor of COX-2. J. Med. Chem. 43, 775 (2000).
  13. Prasit, P., Wang, Z., Brideau, C., Chan, C. C., Charleson, S., Cromlish, W., Ethier, D., Evans, J. F., Ford-Huchinscn, A. W., Gauthier, J. Y., Gordon, R., Guay, J., Gresser, M., Kargman, S., Kennedy, B., Leblanc, Y., Leger, S., Mancini, J., O'Neil, G. P., Ouellet, M., Percival, M. D., Perrier, H., Reindeau, D., Rodger, I., Tagari, P., Therian, M., Vickers, P., Wong, E., Xu, L. J., Visco, D. and Patrick, D. : The discovery of Rofecoxib. MK-996, Vioxx, 4-(4'-thylsulfonylphenyl)-3-phenyl-2(5H)-furanone]. An orally active cyclooxygenase-2 inhibitor. Bioorg. Med. Chem. Lett. 9, 1773 (1999)
  14. Lee, S., Soyoola, E., Chanmugam, P., Hart, S., Sun, W., Zhong, H., Liou, S., Simmons, D. and Hwang, D. : Selective expresstion of mitogen-inducible cyclooxygenase in macrophages stimulated with lipopolysaccaride. J. Biol. Chem. 267, 25934 (1992)
  15. Noh, M., Ha, J., Lee, C., Lee, W., Lee, S. and Lee, J. : Inhibitory activities of natural products on lipopolysaccaride induced prostaglandin production in mouse macrophages. Yakhak Hoeji 42, 558 (1998)
  16. Dray, F., Mamasd, S. and Bizzini B. : Problems of PGD antisera specificity. Meth. Enzymol. 86, 258 (1982)
  17. Xie, W., Chipman, J. G., Robertson, D. L., Erikson, R. L. and Simmons, D. L. : Expression of a mitogen-response gene encoding prostaglandin synthetase is regulated by mRNA splicing. Proc. Natl. Acad. Sci. U.S.A. 89, 3917 (1992) https://doi.org/10.1073/pnas.89.9.3917
  18. Tsuji, K., Nakamura, K., Konishi, N., Tojo, T., Ochi, T., Senoh, H. and Matsuo , M. : Synthesis and pharmacological properties of 1,5-diarylpyrazoles and related derivatives. Chem. Pharm. Bull. 45, 987 (1997)
  19. O'Banion, M. K., Sadowski, H. B., Winn, V. and Young, D. A. : A serum and glucocorticoid regulated 4 kilobase mRNA ecodes a cyclooxygenase related protein. J. Biol. Cham. 266, 23261 (1991)
  20. Kalgutkar, A. S., Marnett, A. B., Crews, B. C., Remmel, R. P. and Marnett, L. J. : Ester and amide derivatives of the nonsteroidal antiinflammatory drugs, Indomethacin, as selective cyclooxygenase-2 Inhibitors. J. Med. Chem. 43, 2860 (2000) https://doi.org/10.1021/jm000004e
  21. Khanna, I. K., Yu, Y., Huff, R. M., Weier, R. M., Xu, X., Koszyk, F. J., Collins, P. W., Cogburn, J. N., Isakson , P. C., Koboldt, C. M., Masferrer, J. L., Perkins , W. E., Siebert, K., Veenhuizen, A. W., Yuan, J., Yang, D. C. and Zhang, Y. Y. : Selective cyclooxygenase-2 inhibitors: Heteroaryl modified 1,2-diaryl-imidazoles are potent, orally active antiinflammatory agents. J. Med. Chem. 43, 3168 (2000)