Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl ] propenamide and related compounds
| Autor: | C. B. Jones, E. A. Kuo, Yea Christopher Martyn, C. J. R. Hedgecock, Peter W. Hairsine, N. Mcdowall, R. A. Williamson, P. Hambleton, W. R. Tully, Robert Westwood, Saroop S. Matharu, Ian R. Ager, David Kay, A. W. E. Chan, P. L. Evans, E. Little |
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| Rok vydání: | 1996 |
| Předmět: |
Male
Oxidoreductases Acting on CH-CH Group Donors Magnetic Resonance Spectroscopy Spectrophotometry Infrared Stereochemistry Dihydroorotate Dehydrogenase chemistry.chemical_compound Mice Structure-Activity Relationship Drug Discovery medicine Animals Hypersensitivity Delayed Enzyme Inhibitors Rats Wistar Active metabolite Dihydroorotate Dehydrogenase Inhibitor Leflunomide chemistry.chemical_classification Acrylamides Trifluoromethyl Anti-Inflammatory Agents Non-Steroidal Biological activity Arthritis Experimental Rats Kinetics Enzyme chemistry Biochemistry Mice Inbred DBA Pyrimidine metabolism Dihydroorotate dehydrogenase Molecular Medicine Female Oxidoreductases medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 39(23) |
| ISSN: | 0022-2623 |
| Popis: | The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED50 = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress. |
| Databáze: | OpenAIRE |
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