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Comparison of two molecular scaffolds, 5-methylisoxazole-3-carboxamide and 5-methylisoxazole-4-carboxamide
- Source :
- Scopus-Elsevier
- Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Toluidines
medicine.drug_class
Metabolite
Hydroxybutyrates
Carboxamide
Pharmacology
chemistry.chemical_compound
Drug Discovery
Teriflunomide
Nitriles
medicine
Toxicity Tests, Acute
Animals
Humans
Active metabolite
Leflunomide
Mutagenicity Tests
Anti-Inflammatory Agents, Non-Steroidal
Isoxazoles
medicine.disease
Acute toxicity
Teratogens
chemistry
Biochemistry
Rheumatoid arthritis
Crotonates
Dihydroorotate dehydrogenase
medicine.drug
Subjects
Details
- ISSN :
- 18734286
- Volume :
- 20
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Current pharmaceutical design
- Accession number :
- edsair.doi.dedup.....d33b2abbf10cf392319cffdacde6dce8