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Chemical Compound Review

Flucyamide     (2E)-2-[hydroxy-[[4- (trifluoromethyl)pheny...

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Disease relevance of A771726

  • The rank order of potency of A77 1726 and its analogues in binding or enzyme inhibition was similar to that for inhibition of the mouse delayed type hypersensitivity response [1].
  • A77 1726 induces differentiation of human myeloid leukemia K562 cells by depletion of intracellular CTP pools [2].
  • METHODS AND RESULTS: Plaque assay of virus yield from endothelial or Vero cells after inoculation with each of four clinical HSV-1 isolates demonstrated a dose-dependent reduction of virus production in the presence of pharmacologic concentrations of A77 1726, the active metabolite of leflunomide [3].
  • Addition of either one of three different inhibitors of NFkappaB (SN50, PDTC, and A771726) to mouse TNF-alpha sensitized WEG-1 cells to the toxicity of the cytokine [4].
  • Accordingly to results obtained with primary astrocytes, both A77 1726 and PD98059 significantly reduced IFN-gamma+LPS-induced NO synthesis in the cultures of rat astrocytoma cell line C6 [5].

High impact information on A771726


Chemical compound and disease context of A771726

  • The relative lack of toxicity of A77 1726 on nonlymphoid cells may be due to the ability of these cells to fulfill their ribonucleotide requirements by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis [9].

Biological context of A771726


Anatomical context of A771726

  • Here murine CTLL cell lines were studied to determine which of the biochemical targets of A77 1726 was responsible for the observed inhibition of proliferation and cytotoxic activity [10].
  • The T-cell receptor-mediated in vitro activatability of a P2-specific T-cell hybridoma was diminished by high concentrations of A77 1726, as evidenced by reduced Ca(2+) flux into the cytosol [8].
  • The human high-affinity binding protein for radiolabelled A77 1726 was purified from solubilized U937 membranes by following the binding activity through the purification process and was characterized as the mitochondrial enzyme dihydro-orotate dehydrogenase (DHO-DH) [14].
  • A77 1726 suppressed the production of SAA in human hepatocytes activated by IL-1beta in a dose-dependent manner (0-50 microM) [15].
  • The extracellular concentration of TNFalpha was found to be significantly decreased in media containing cultured macrophages at 24 hours for all tested doses of A77 1726 [16].

Associations of A771726 with other chemical compounds


Gene context of A771726


Analytical, diagnostic and therapeutic context of A771726

  • BACKGROUND: FK778, a derivative of the active leflunomide-metabolite, A77 1726, has been shown to be a powerful immunosuppressant in several transplantation models, particularly efficient in the prevention of chronic allograft rejection [22].
  • Therapeutic drug monitoring of A77 1726 may be useful in predicting the efficacy of leflunomide treatment [23].
  • Effects of leflunomide were evaluated by two treatment protocols: mice treated with MLD-SZ were injected intraperitoneally with A77 1726 for 10 consecutive days, either during the first 10 days of the disease (early treatment), or starting from day 10 after disease induction (late treatment) [24].
  • A rapid and simple determination of A77 1726 in human serum by high-performance liquid chromatography and its application for optimization of leflunomide therapy [25].
  • This study was conducted to investigate the importance of direct contact between Kupffer cells (KCs) and hepatocytes (HCs) during the hepatic inflammatory responses, and the effect of leflunomide's active metabolite, A771726, on cytokines in KCs and HCs (DC cocultures) and KC cultures using an in vitro approach [26].


  1. Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound. Williamson, R.A., Yea, C.M., Robson, P.A., Curnock, A.P., Gadher, S., Hambleton, A.B., Woodward, K., Bruneau, J.M., Hambleton, P., Moss, D., Thomson, T.A., Spinella-Jaegle, S., Morand, P., Courtin, O., Sautés, C., Westwood, R., Hercend, T., Kuo, E.A., Ruuth, E. J. Biol. Chem. (1995) [Pubmed]
  2. A77 1726 induces differentiation of human myeloid leukemia K562 cells by depletion of intracellular CTP pools. Huang, M., Wang, Y., Collins, M., Mitchell, B.S., Graves, L.M. Mol. Pharmacol. (2002) [Pubmed]
  3. Inhibition of herpes simplex virus type 1 by the experimental immunosuppressive agent leflunomide. Knight, D.A., Hejmanowski, A.Q., Dierksheide, J.E., Williams, J.W., Chong, A.S., Waldman, W.J. Transplantation (2001) [Pubmed]
  4. Activation of nuclear factor kappaB and induction of apoptosis by tumor necrosis factor-alpha in the mouse uterine epithelial WEG-1 cell line. Pampfer, S., Cordi, S., Cikos, S., Picry, B., Vanderheyden, I., Hertogh, R.D. Biol. Reprod. (2000) [Pubmed]
  5. Leflunomide inhibits activation of inducible nitric oxide synthase in rat astrocytes. Miljkovic, D., Samardzic, T., Mostarica Stojkovic, M., Stosic-Grujicic, S., Popadic, D., Trajkovic, V. Brain Res. (2001) [Pubmed]
  6. Disruption of the interaction of T cells with antigen-presenting cells by the active leflunomide metabolite teriflunomide: involvement of impaired integrin activation and immunologic synapse formation. Zeyda, M., Poglitsch, M., Geyeregger, R., Smolen, J.S., Zlabinger, G.J., Hörl, W.H., Waldhäusl, W., Stulnig, T.M., Säemann, M.D. Arthritis Rheum. (2005) [Pubmed]
  7. Malarial dihydroorotate dehydrogenase. Substrate and inhibitor specificity. Baldwin, J., Farajallah, A.M., Malmquist, N.A., Rathod, P.K., Phillips, M.A. J. Biol. Chem. (2002) [Pubmed]
  8. Suppression of experimental autoimmune neuritis by leflunomide. Korn, T., Toyka, K., Hartung, H.P., Jung, S. Brain (2001) [Pubmed]
  9. Mechanism of action for leflunomide in rheumatoid arthritis. Fox, R.I., Herrmann, M.L., Frangou, C.G., Wahl, G.M., Morris, R.E., Strand, V., Kirschbaum, B.J. Clin. Immunol. (1999) [Pubmed]
  10. The immunosuppressive metabolite of leflunomide, A77 1726, affects murine T cells through two biochemical mechanisms. Elder, R.T., Xu, X., Williams, J.W., Gong, H., Finnegan, A., Chong, A.S. J. Immunol. (1997) [Pubmed]
  11. Inhibition of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients with rheumatoid arthritis: findings in a prospective, randomized, double-blind clinical trial in fifteen patients. Kraan, M.C., de Koster, B.M., Elferink, J.G., Post, W.J., Breedveld, F.C., Tak, P.P. Arthritis Rheum. (2000) [Pubmed]
  12. Multiple inhibitor analysis of the brequinar and leflunomide binding sites on human dihydroorotate dehydrogenase. McLean, J.E., Neidhardt, E.A., Grossman, T.H., Hedstrom, L. Biochemistry (2001) [Pubmed]
  13. Two activities of the immunosuppressive metabolite of leflunomide, A77 1726. Inhibition of pyrimidine nucleotide synthesis and protein tyrosine phosphorylation. Xu, X., Williams, J.W., Gong, H., Finnegan, A., Chong, A.S. Biochem. Pharmacol. (1996) [Pubmed]
  14. Purification of human dihydro-orotate dehydrogenase and its inhibition by A77 1726, the active metabolite of leflunomide. Bruneau, J.M., Yea, C.M., Spinella-Jaegle, S., Fudali, C., Woodward, K., Robson, P.A., Sautès, C., Westwood, R., Kuo, E.A., Williamson, R.A., Ruuth, E. Biochem. J. (1998) [Pubmed]
  15. An active metabolite of leflunomide, A77 1726, inhibits the production of serum amyloid A protein in human hepatocytes. Migita, K., Miyashita, T., Maeda, Y., Nakamura, M., Yatsuhashi, H., Ishibashi, H., Eguchi, K. Rheumatology (Oxford, England) (2005) [Pubmed]
  16. Anti-inflammatory effects of leflunomide on cultured synovial macrophages from patients with rheumatoid arthritis. Cutolo, M., Sulli, A., Ghiorzo, P., Pizzorni, C., Craviotto, C., Villaggio, B. Ann. Rheum. Dis. (2003) [Pubmed]
  17. In vivo activity of leflunomide: pharmacokinetic analyses and mechanism of immunosuppression. Chong, A.S., Huang, W., Liu, W., Luo, J., Shen, J., Xu, W., Ma, L., Blinder, L., Xiao, F., Xu, X., Clardy, C., Foster, P., Williams, J.A. Transplantation (1999) [Pubmed]
  18. The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Davis, J.P., Cain, G.A., Pitts, W.J., Magolda, R.L., Copeland, R.A. Biochemistry (1996) [Pubmed]
  19. Leflunomide, a novel immunomodulating agent, prevents the development of allergic sensitization in an animal model of allergic asthma. Eber, E., Uhlig, T., McMenamin, C., Sly, P.D. Clin. Exp. Allergy (1998) [Pubmed]
  20. Leflunomide: mode of action in the treatment of rheumatoid arthritis. Breedveld, F.C., Dayer, J.M. Ann. Rheum. Dis. (2000) [Pubmed]
  21. The active metabolite of leflunomide, A77 1726, inhibits the production of prostaglandin E(2), matrix metalloproteinase 1 and interleukin 6 in human fibroblast-like synoviocytes. Burger, D., Begué-Pastor, N., Benavent, S., Gruaz, L., Kaufmann, M.T., Chicheportiche, R., Dayer, J.M. Rheumatology (Oxford, England) (2003) [Pubmed]
  22. Inhibition of human dendritic cell maturation and function by the novel immunosuppressant FK778. Zeyda, M., Kirsch, B.M., Geyeregger, R., Stuhlmeier, K.M., Zlabinger, G.J., Hörl, W.H., Säemann, M.D., Stulnig, T.M. Transplantation (2005) [Pubmed]
  23. Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: serum concentrations predict response to treatment in patients with rheumatoid arthritis. van Roon, E.N., Jansen, T.L., van de Laar, M.A., Janssen, M., Yska, J.P., Keuper, R., Houtman, P.M., Brouwers, J.R. Ann. Rheum. Dis. (2005) [Pubmed]
  24. Leflunomide protects mice from multiple low dose streptozotocin (MLD-SZ)-induced insulitis and diabetes. Stosic-Grujicic, S., Dimitrijevic, M., Bartlett, R. Clin. Exp. Immunol. (1999) [Pubmed]
  25. A rapid and simple determination of A77 1726 in human serum by high-performance liquid chromatography and its application for optimization of leflunomide therapy. van Roon, E.N., Yska, J.P., Raemaekers, J., Jansen, T.L., van Wanrooy, M., Brouwers, J.R. Journal of pharmaceutical and biomedical analysis. (2004) [Pubmed]
  26. A 771726, the active metabolite of leflunomide, inhibits TNF-alpha and IL-1 from Kupffer cells. Yao, H.W., Li, J., Chen, J.Q., Xu, S.Y. Inflammation (2004) [Pubmed]
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