SYNTHESIS, STRUCTURE-ACTIVITY-RELATIONSHIPS, AND PHARMACOKINETIC PROPERTIES OF DIHYDROOROTATE DEHYDROGENASE INHIBITORS - -[3'-METHYL-4'-(TRIFLUOROMETHYL)PHENYL]PROPENAMIDE AND RELATED-COMPOUNDS

The active metabolite (2) of the novel immunosuppressive agent lefluno mide (1) has been shown to inhibit the enzyme dihydroorotate dehydroge nase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimid ine biosynthesis. A series of analogues of the active metabolite 2 hav e been synthesized. Their in vivo biological activity determined in ra t 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 (ED(50) = 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.