Archives of Pharmacal Research

, Volume 26, Issue 3, pp 197–201 | Cite as

Synthesis of β-hydroxy-propenamide derivatives and the inhibition of human dihydroorotate dehydrogenase

  • Taek Hyeon Kim
  • Hye -Sun Na
  • Monika Löffler
Research Article Articles


Novel β-hydroxy propenamides as analogues of the active metabolite of leflunomide (A 771726) were synthesized and evaluated for their inhibitory activity on dihydroorotate dehydrogenase (DHODH) in an investigation into their immunosuppressive activity. Compounds2a, 3a, and3h were approximately 4–40 times more potent than leflunomide in their activity while they wereless active than A 771726.

Key words

Immunosuppressive activity A 771726 Leflunomide Succinyl acetone β-Hydroxy propenamides Dihydroorotate dehydrogenase (DHODH) 


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  1. Bertolini, G., Aquino, M., Biffi, M., dAtri, G., Di Pierro, F., Ferrario, F., Mascagni, P., Somenzi, F., Zaliani, A., and Leoni, F., A new rational hypothesis for the pharmacophore of the active metabolite of leflunomide, a potent immunosuppressive drug.J. Med. Chem., 40, 2011–2016 (1997).PubMedCrossRefGoogle Scholar
  2. Borel, J. F., History of cyclosporin A and its significance in immunology. In cyclosporin A, Borel, J. F., Ed.; Elsevier Biochemical Press: Amsterdam, 1982, pp 5–17.Google Scholar
  3. Davis, J. P., Cain, G. A., Pitts, W. J., Magolda, R. L., and Copeland, R. A., The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase.Biochemistry, 35, 1270–1273 (1996).PubMedCrossRefGoogle Scholar
  4. Elison, G. B. and Hitchings G. H., Azathioprine.Handb. Exp. Pharmacol., 38, 404–425 (1975).Google Scholar
  5. Fidler, J. M., Chang, T. G., Bauer, R., Young, J. D., and Vitt, C. R., Suppression of graft-versus-host disease by succinylacetone in a rat allogeneic bone marrow transplantation model.Transplantation, 55, 367–373 (1993).PubMedCrossRefGoogle Scholar
  6. Hess, R. A., Tschudy, D. P., and Blaese, R. M., Immunosuppression by succinylacetone: II. prevention of graft-vs-host disease.J. Immunol., 139, 2845–2849 (1987).PubMedGoogle Scholar
  7. Jones, M. E., Pyrimidine nucleotide biosynthesis in animals, genes, enzymes, and regulation of UMP biosynthesis.Annu, Rev. Biochem., 49, 253–256 (1980).CrossRefGoogle Scholar
  8. Knecht, W., Bergjohann, U., Gonski, S., Kirschbaum, B., and Loffler, M., Functional expression of a fragment of human dihydroorotate dehydrogenase by means of the baculovius vector system, and kinetic investigation of the purified enzyme.Eur. J. Biochem., 240, 292–301 (1996).PubMedCrossRefGoogle Scholar
  9. Knecht, W. and Löffler, M., Species-related inhibition of human and rat dihydroorotate dehydrogenase by immunosuppressive isoxazole and cinchoninic acid derivatives.Biochem. Pharmacol., 56, 1259–1264 (1998).PubMedCrossRefGoogle Scholar
  10. Kuo, E. A., Hambleton, P. T., Kay, D. P., Evans, P. L., Matharu, S. S., Little, E., McDowall, N., Jones, C. B., Hedgecock, C. J. R., Yea, C. M., Chan, A. W. E., Hairsine, P. W., Ager, I. R., Tully, W. R., Williamson, R. A., and Westwood, R., Synthesis, structure-activity relationship, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3-methyl-4-(trifluoromethyl)phenyl] propenamide and related compounds.J. Med. Chem., 39, 4608–4621 (1996).PubMedCrossRefGoogle Scholar
  11. Lindblad, B., Lindstedt, S., and Steen, G., On the enzyme defects in hereditary tyrosinemia.Proc. Natl. Acad. Sci. USA, 74, 4641–4645 (1977)PubMedCrossRefGoogle Scholar
  12. Papageorgiou, C., Zurini, M., Weber, H.-P., and Borer, X., Leflunomides bioactive metabolite has the minimal structural requirement for the efficient inhibition of human dihydroorotate dehydrogenase.Bioorg. Chem., 25, 233–238 (1997).CrossRefGoogle Scholar
  13. Perico, N. and Remuzzi, G., Prevention of transplant rejection current treatment guidelines and future developments.Drugs, 54, 533–570 (1997).PubMedCrossRefGoogle Scholar
  14. Sanders, S. and Harisdangkul, V., Leflunomide for the treatment of rheumatoid arthritis and autoimmunity.Am. J. Med. Sci., 323, 190–193 (2002).PubMedCrossRefGoogle Scholar
  15. Shaw, L. M., Kaplan, B., and Kaufman, D., Toxic effects of immunosuppressive drugs: mechanism and strategies for controlling them.Clin. Chem., 42, 1316–1321 (1996).PubMedGoogle Scholar
  16. Skolik, S. A., Palestine, A. G., Blaese, R. M. Nussenblatt, R. B., and Hess, R. A., Treatment of experimental autoimmune uveitis in the rat with systemic succinylacetone.Clin. Immunol. Immunopathol., 49, 63–71 (1988).PubMedCrossRefGoogle Scholar
  17. Tanaka, H., Kuroda, A., Marusawa, H., Hatanaka, H., Kino, T., Goto, T., Hashimoto, M., and Taga, T., Structure of FK506: a novel immunosuppressants isolated fro.Streptomyces. J. Am. Chem. Soc., 109, 5031–5033 (1987).CrossRefGoogle Scholar
  18. Tschudy, D. P., Hess, R., Frykholm, B., and Blaese, R. M., Immunosuppressive activity of succinylacetone.J. Lab. Clin. Med., 99, 526–532 (1981).Google Scholar

Copyright information

© The Pharmaceutical Society of Korea 2003

Authors and Affiliations

  • Taek Hyeon Kim
    • 1
  • Hye -Sun Na
    • 1
  • Monika Löffler
    • 2
  1. 1.Department of Applied Chemistry, College of EngineeringChonnam National UniversityGwangjuKorea
  2. 2.Institute for Physiological Chemistry, School of MedicinePhilipps-UniversityMarburgGermany

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