Details
Stereochemistry | ACHIRAL |
Molecular Formula | C12H9F3N2O2 |
Molecular Weight | 270.2073 |
Optical Activity | NONE |
Defined Stereocenters | 0 / 0 |
E/Z Centers | 1 |
Charge | 0 |
Stereo Comments | Teriflunomide then can interconvert between the E and Z enolic forms (and the corresponding keto-amide), with the Z-enol being the most stable and therefore most predominant form (https://en.wikipedia.org/wiki/Leflunomide) |
SHOW SMILES / InChI
SMILES
C\C(O)=C(/C#N)C(=O)NC1=CC=C(C=C1)C(F)(F)F
InChI
InChIKey=UTNUDOFZCWSZMS-YFHOEESVSA-N
InChI=1S/C12H9F3N2O2/c1-7(18)10(6-16)11(19)17-9-4-2-8(3-5-9)12(13,14)15/h2-5,18H,1H3,(H,17,19)/b10-7-
Leflunomide is a pyrimidine synthesis inhibitor belonging to the DMARD (disease-modifying antirheumatic drug) class of drugs, which are chemically and pharmacologically very heterogeneous. Leflunomide was approved by FDA and in many other countries. Leflunomide is an isoxazole immunomodulatory agent that inhibits dihydroorotate dehydrogenase (a mitochondrial enzyme involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro experimental models have demonstrated an anti-inflammatory effect. Leflunomide is rapidly metabolized to its active form, teriflunomide (A77 1726). Two mechanisms of action have been identified for A77 1726: inhibition of dihydroorotate dehydrogenase (DHODH) and inhibition of tyrosine kinases. DHODH inhibition occurs at lower concentrations of A77 1726 than that of tyrosine kinases and is currently considered the major mode of action. Human dihydroorotate dehydrogenase consists of 2 domains: an α/β-barrel domain containing the active site and an α-helical domain that forms a tunnel leading to the active site. A77 1726 binds to the hydrophobic tunnel at a site near the flavin mononucleotide. Inhibition of dihydroorotate dehydrogenase by A77 1726 prevents production of rUMP by the de novo pathway; such inhibition leads to decreased rUMP levels, decreased DNA and RNA synthesis, inhibition of cell proliferation, and G1 cell cycle arrest. It is through this action that leflunomide inhibits autoimmune T-cell proliferation and production of autoantibodies by B cells. Since salvage pathways are expected to sustain cells arrested in the G1 phase, the activity of leflunomide is cytostatic rather than cytotoxic. Tyrosine kinases activate signalling pathways leading to DNA repair, apoptosis and cell proliferation. Inhibition of tyrosine kinases can help to treating cancer by preventing repair of tumor cells. Teriflunomide is also an inhibitor of CYP2C8 in vivo. In patients taking leflunomide, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking leflunomide, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking leflunomide.
CNS Activity
Originator
Approval Year
PubMed
Title | Date | PubMed |
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Structural and functional comparison of agents interfering with dihydroorotate, succinate and NADH oxidation of rat liver mitochondria. | 1998 Oct 15 |
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Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. | 1999 Feb 15 |
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Vasculitis occurring during leflunomide therapy. | 2001 |
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The heterotopic tracheal allograft as an animal model of obliterative bronchiolitis. | 2001 |
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A randomized, controlled, single-blind trial of leflunomide in the treatment of rheumatoid arthritis. | 2001 |
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Leflunomide and rheumatoid arthritis: new preparation. Neither the safest nor the most effective slow-acting antirheumatic drug. | 2001 Apr |
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Novel therapies in the treatment of systemic lupus erythematosus. | 2001 Aug |
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[Leflunomide plus methotrexate. Hope for patients with rheumatoid arthritis]. | 2001 Aug 23 |
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Leflunomide-mediated suppression of antiviral antibody and Tcell responses: differential restoration by uridine. | 2001 Aug 27 |
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[New basic therapeutic drugs from the viewpoint of evidence-based therapy]. | 2001 Dec |
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[Evidence-based medicine and applying new therapies in general practice: wish and reality]. | 2001 Dec |
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Progress in the treatment of rheumatoid arthritis. | 2001 Dec 12 |
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Leflunomide Aventis Pharma. | 2001 Feb |
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Discussion. Treatment algorithm: managing rheumatoid arthritis. | 2001 Jul |
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Economic and quality-of-life impact of rheumatoid arthritis. | 2001 Jul |
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Hamster cardiac xenografts are protected against antibody mediated damage, early after transplantation to Lewis rats. | 2001 Nov |
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Rationally designed anti-mitotic agents with pro-apoptotic activity. | 2001 Nov |
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[Leflunomide--a new disease modifying anti-rheumatic agent]. | 2001 Nov 10 |
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Inhibition of angiogenesis-related endothelial activity by the experimental immunosuppressive agent leflunomide. | 2001 Nov 15 |
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Use of leflunomide in human renal transplantation. | 2001 Nov 27 |
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Severe liver damage with leflunomide. | 2001 Oct |
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[New therapy developments in rheumatoid arthritis]. | 2001 Oct |
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Platelet-derived growth factor receptors: a therapeutic target in solid tumors. | 2001 Oct |
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Current and emerging lupus treatments. | 2001 Oct |
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Leflunomide for the treatment of systemic lupus erythematosus: comment on the article by McMurray. | 2001 Oct |
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Treatment of active rheumatoid arthritis with leflunomide: two year follow up of a double blind, placebo controlled trial versus sulfasalazine. | 2001 Oct |
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Inhibition of HIV replication by A77 1726, the active metabolite of leflunomide, in combination with pyrimidine nucleoside reverse transcriptase inhibitors. | 2001 Oct 1 |
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Is there a place for leflunomide in the treatment of rheumatoid arthritis? | 2001 Oct 13 |
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Nerve injury proximal or distal to the DRG induces similar spinal glial activation and selective cytokine expression but differential behavioral responses to pharmacologic treatment. | 2001 Oct 15 |
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Comparison of rheumatoid arthritis care costs in patients starting therapy with leflunomide versus etanercept. | 2001 Sep |
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Two-year, blinded, randomized, controlled trial of treatment of active rheumatoid arthritis with leflunomide compared with methotrexate. Utilization of Leflunomide in the Treatment of Rheumatoid Arthritis Trial Investigator Group. | 2001 Sep |
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Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study. | 2001 Sep |
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Suppression of experimental autoimmune neuritis by leflunomide. | 2001 Sep |
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[Treatment of rheumatoid arthritis by inhibition of tumor necrosis factor with infliximab or etanercept]. | 2001 Sep 29 |
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Treating rheumatoid arthritis with new disease modifying drugs. | 2002 |
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Treatment of severe psoriasis and psoriatic arthritis with leflunomide. | 2002 Feb |
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Comparative assessment of leflunomide and methotrexate for the treatment of rheumatoid arthritis, by dynamic enhanced magnetic resonance imaging. | 2002 Feb |
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Experiences with leflunomide in solid organ transplantation. | 2002 Feb 15 |
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[Treatment of cutaneous leishmaniasis--an update]. | 2002 Jan |
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Leflunomide induced fevers, thrombocytosis, and leukocytosis in a patient with relapsing polychondritis. | 2002 Jan |
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Effect of hemodialysis on leflunomide plasma concentrations. | 2002 Jan |
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Update on the treatment of systemic lupus erythematosus: therapeutic highlights from the Sixth International Lupus Conference. | 2002 Jan |
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Current treatment of juvenile rheumatoid arthritis. | 2002 Jan |
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A77 1726 induces differentiation of human myeloid leukemia K562 cells by depletion of intracellular CTP pools. | 2002 Sep |
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[The active metabolite of leflunomide A771726 inhibits proliferation and collagen synthesis of hepatic stellate cell]. | 2004 Nov |
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Design and synthesis of potent inhibitors of the malaria parasite dihydroorotate dehydrogenase. | 2007 Jan 25 |
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The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells. | 2008 Mar |
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Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminishes proliferation of multiple myeloma cells. | 2009 Feb |
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Hepatic cytochrome P450s attenuate the cytotoxicity induced by leflunomide and its active metabolite A77 1726 in primary cultured rat hepatocytes. | 2011 Aug |
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Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. | 2015 May 18 |
Patents
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Classification Tree | Code System | Code | ||
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LIVERTOX |
940
Created by
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WHO-VATC |
QL04AA31
Created by
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NCI_THESAURUS |
C471
Created by
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EMA ASSESSMENT REPORTS |
AUBAGIO (AUTHORIZED: MULTIPLE SCLEROSIS)
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NDF-RT |
N0000185502
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WHO-ATC |
L04AA31
Created by
admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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Code System | Code | Type | Description | ||
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DB08880
Created by
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PRIMARY | |||
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163451-81-8
Created by
admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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PRIMARY | |||
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54684141
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SUB25218
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admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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C527525
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admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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TERIFLUNOMIDE
Created by
admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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7761
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admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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N0000185501
Created by
admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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PRIMARY | Dihydroorotate Dehydrogenase Inhibitors [MoA] | ||
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M10578
Created by
admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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PRIMARY | Merck Index | ||
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CHEMBL973
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108605-62-5
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admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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NON-SPECIFIC STEREOCHEMISTRY | |||
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C76662
Created by
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6844
Created by
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1310520
Created by
admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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PRIMARY | RxNorm | ||
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163451-81-8
Created by
admin on Mon Oct 21 22:16:45 UTC 2019 , Edited by admin on Mon Oct 21 22:16:45 UTC 2019
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PRIMARY |
ACTIVE MOIETY
METABOLITE (PARENT)
METABOLITE (PARENT)