Synthesis of β-hydroxy-propenamide derivatives and the inhibition of human dihydroorotate dehydrogenase
- 80 Downloads
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 wordsImmunosuppressive activity A 771726 Leflunomide Succinyl acetone β-Hydroxy propenamides Dihydroorotate dehydrogenase (DHODH)
Unable to display preview. Download preview PDF.
- 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
- 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
- Elison, G. B. and Hitchings G. H., Azathioprine.Handb. Exp. Pharmacol., 38, 404–425 (1975).Google Scholar
- 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
- 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
- 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