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

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). 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. 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). Elison, G. B. and Hitchings G. H., Azathioprine.Handb. Exp. Pharmacol., 38, 404–425 (1975). 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). 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). Jones, M. E., Pyrimidine nucleotide biosynthesis in animals, genes, enzymes, and regulation of UMP biosynthesis.Annu, Rev. Biochem., 49, 253–256 (1980). 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). 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). 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). Lindblad, B., Lindstedt, S., and Steen, G., On the enzyme defects in hereditary tyrosinemia.Proc. Natl. Acad. Sci. USA, 74, 4641–4645 (1977) 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). Perico, N. and Remuzzi, G., Prevention of transplant rejection current treatment guidelines and future developments.Drugs, 54, 533–570 (1997). Sanders, S. and Harisdangkul, V., Leflunomide for the treatment of rheumatoid arthritis and autoimmunity.Am. J. Med. Sci., 323, 190–193 (2002). 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). 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). 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). Tschudy, D. P., Hess, R., Frykholm, B., and Blaese, R. M., Immunosuppressive activity of succinylacetone.J. Lab. Clin. Med., 99, 526–532 (1981).