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.
Keywords: Leflunomide, UTL-5 series, metabolite, DHODH, liver toxicity, teratogenicity
Current Pharmaceutical Design
Title:Comparison of Two Molecular Scaffolds, 5-Methylisoxazole-3-Carboxamide and 5-Methylisoxazole-4-Carboxamide
Volume: 20 Issue: 1
Author(s): Yaoming Song, Yiguan Zhang, An-Rong Lee, Wen-Hsin Huang, Ben Chen, Bruce Palfey and Jiajiu Shaw
Affiliation:
Keywords: Leflunomide, UTL-5 series, metabolite, DHODH, liver toxicity, teratogenicity
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.
Export Options
About this article
Cite this article as:
Song Yaoming, Zhang Yiguan, Lee An-Rong, Huang Wen-Hsin, Chen Ben, Palfey Bruce and Shaw Jiajiu, Comparison of Two Molecular Scaffolds, 5-Methylisoxazole-3-Carboxamide and 5-Methylisoxazole-4-Carboxamide, Current Pharmaceutical Design 2014; 20 (1) . https://dx.doi.org/10.2174/13816128113199990584
DOI https://dx.doi.org/10.2174/13816128113199990584 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Biosimilars for the Management of Inflammatory Bowel Diseases: Economic Considerations
Current Medicinal Chemistry Biomarkers of Senescence during Aging as Possible Warnings to Use Preventive Measures
Current Medicinal Chemistry Involvement of the P2X7 Purinergic Receptor in Inflammation: An Update of Antagonists Series Since 2009 and their Promising Therapeutic Potential
Current Medicinal Chemistry PET Imaging of Opioid Receptors in Pain: Progress and New Directions
Current Pharmaceutical Design Periarticular Corticosteroid Treatment of the Sacroiliac Joint
Current Rheumatology Reviews Total Ankle Replacement in Hemophilia
Cardiovascular & Hematological Disorders-Drug Targets Inflamm-ageing and senescence in gout: the tale of an old king’s disease.
Current Aging Science Non-Canonical Peptides Bound to MHC
Current Pharmaceutical Design Cyclodextrins as Complexation Agents to Improve the Anti-inflammatory Drugs Profile: a Systematic Review and Meta-Analysis
Current Pharmaceutical Design Resisting the Sun with Vitamin D
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Epigenetics and Sjogren’s Syndrome
Current Pharmaceutical Biotechnology Editorial (Thematic Issues: Heads Or Tails: Betting On CD6 As a Resurged Target For Autoimmune Diseases and Sepsis)
Current Drug Targets Parkinson’s Disease: Is there a Role for Dietary and Herbal Supplements?
CNS & Neurological Disorders - Drug Targets The Emerging Potential of By-Products as Platforms for Drug Delivery Systems
Current Drug Targets The Immunoproteasome: An Emerging Therapeutic Target
Current Topics in Medicinal Chemistry HCV-Related Rheumatic Manifestations and Therapeutic Strategies
Current Drug Targets Synthesis and Immunomodulation of Human Lymphocyte Proliferation and Cytokine (Interferon-γ) Production of Four Novel Leflunomide Analogues
Medicinal Chemistry Recent Advances in the Imaging of Programmed Cell Death
Current Pharmaceutical Design COX-2 Selectivity and Inflammatory Processes
Current Medicinal Chemistry Long Noncoding RNA GAS5: A Novel Marker Involved in Glucocorticoid Response
Current Molecular Medicine