A NEW RATIONAL HYPOTHESIS FOR THE PHARMACOPHORE OF THE ACTIVE METABOLITE OF LEFLUNOMIDE, A POTENT IMMUNOSUPPRESSIVE DRUG

Leflunomide is one of the most promising disease-modifying antirheumat ic drug now in clinical trials for the treatment of rheumatoid arthrit is. Metabolic studies have indicated that leflunomide is rapidly proce ssed in vivo to an active metabolite, A771726 (2). To identify the che mical characteristics necessary for the immunosuppressive activity of 2, configurational and conformational studies were carried out on the latter and its inactive analogues (ethyl ((4-(trifluoromethyl)phenyl)c arbamoyl)but-2-enoate 3a, and -hydroxy-2-nitro-N(4-(trifluoromethyl)ph enyl)but-2 -enamide, 3b). These studies suggested that the pharmacopho re responsible for the immunosuppressive activity of 2 is a beta-keto amide with the enolic hydroxy group cis to the amidic moiety. To verif y this hypothesis, a new class of immunosuppressive agents was designe d and synthesized. Their testing in vitro and in vivo identified compo unds which were more potent than both leflunomide and 2 and above all confirmed our hypothesis as to the key structural and chemical determi nants for the immunosuppressive properties of 2 and our compounds.