Leflunomide is a disease-modifying antirheumatic drug (DMARD) for the treatment of rheumatoid arthritis (RA). Structurally,
it is a derivative of 5-methylisoxazole-4-carboxamide. Upon metabolism, the N-O bond in the isoxazole ring is cleaved to form the active
metabolite, teriflunomide, which was recently approved by the FDA for the treatment of multiple sclerosis. Both leflunomide and
teriflunomide inhibit dihydroorotate dehydrogenase (DHODH) thereby inhibiingt the synthesis of pyrimidine. For both drugs, the two
major concerns are potential liver toxicity and teratogenicity. It was suspected that these undesirable effects might be related to the cleavage
of the N-O bond. We herein summarize the metabolites-toxicity issues related to leflunomide/teriflunomide and discuss two related
molecular platforms, UTL-4 and UTL-5. UTL-4 compounds are based on the same scaffold of leflunomide; their toxicological and pharmacological
effects are not significantly different from those of leflunomide/teriflunomide. In UTL-5 series, the leflunomide scaffold is
changed into 5-methylisoxazole-3-carboxamide. Unlike leflunomide, the N-O bond of a UTL-5 compound, UTL-5b, is not cleaved upon
metabolism; instead, the peptide bond is cleaved to form its major metabolites. UTL-5b and its metabolites do not inhibit DHODH in vitro.
In addition, UTL-5b and all other UTL-5 compounds have lower acute toxicity than leflunomide/teriflunomide. Furthermore, from
leflunomide to UTL-5b/UTL-5g, the potential liver toxicity becomes liver protective effect. With the reduced toxicity, UTL-5 compounds
still maintain significant pharmacological effects including anti-inflammatory and antiarthritic effects. In summary, our observations
provide a valuable direction in drug optimization based on the modification of the leflunomide scaffold.