l-5,6-Dihydroorotate; an intermediate in the biosynthesis of pyrimidines.
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10) Leflunomide inhibits an enzyme in the pyrimidine pathway, dihydroorotate dehydrogenase.
Pipeline candidates fall under a variety of major therapeutic classes such as p38 kinase inhibitors, Janus Kinase Inhibitors (JAK), tyrosine kinase inhibitors, dihydrofolate reductase inhibitors, cyclooxygenase (COX) inhibitors, Dihydroorotate dehydrogenase (DHODH) inhibitors, interleukin inhibitors, tumor necrosis factor (TNF) inhibitors, chemotaxis inhibitors, Vascular Adhesion Protein-1 (VAP 1) inhibitors, granulocyte macrophage colony stimulating factor (GM-CSF) inhibitors, Toll-like receptors (TLRs) and anti-CD 20 monoclonal antibodies.
Mechanism of action of leflunomide in the treatment of RA is selectively inhibition of enzyme dihydroorotate dehydrogenase that is necessary for the de novo pyrimidine synthesis (2).
Researchers at the University of Leeds say that the compounds work by preventing the enzyme dihydroorotate dehydrogenase (DHODH) - essential to the growth of the parasite - from working, which results in its death.
The addition of dichloroallyl lawsone (DCL) to leukemic cells results in a rapid depletion of uridine and cytidine nucleotides; carbamyl aspartate and dihydroorotate accumulate to high levels in an equilibrium ratio of 20.
A Medicinal Chemistry Program for the Discovery of Plasmodium Falciparum Dihydroorotate Dehydrogenase Inhibitors with Antimalarial Activity
Drug classes and targets: NSAIDs, DMARDs, cyclooxygenase-2 (COX-2), CD20, interleukin-6 receptor (IL-6R), tumor necrosis factor-alpha (TNF-a), B-lymphocyte-stimulator (BLyS), B-cellactivating factor (BAFF), spleen tyrosine kinase (syk), small nuclear ribonucleoparticle peptide, CD22, Jak-3 kinase, cyclooxygenase-inhibiting nitric oxide donator (CINOD), endothelin receptor, dihydroorotate dehydrogenase (DHODH), hyaluronic acid, xanthine oxidase, fibroblast growth factor-18, interleukin-20 (IL-20), C5aR receptor, interleukin-6 (IL-6), CD40L.
4SC-101 inhibits dihydroorotate dehydrogenase (DHODH), which acts as a highly selective inhibitor of the biosynthesis of pyrimidines, thereby halting the proliferation of rapidly multiplying cells, in particular of lymphocytes which are involved in the pathology of autoimmune disorders.
4SC AG ("4SC"), a German-based drug discovery and development company, and Serono (virt-x: SEO and NYSE: SRA) announced today that they have signed an agreement under which 4SC grants Serono exclusive worldwide rights to develop and commercialize 4SC's program of dihydroorotate dehydrogenase (DHODH) inhibitors.
Unlike currently available immunosuppressants, FK778 exerts its immunosuppressive activity at the molecular level via the suppression of de-novo pyrimidine biosynthesis, inhibiting the action of dihydroorotate dehydrogenase, an enzyme critical in the process, and consequently inhibiting cell proliferation.
Key classes of mechanism of action includes Interleukin inhibitors, Kinase inhibitors, cytokine targetters, TNF targetters, C5a receptor antagonists, Cathepsin inhibitors, Histone deacetylase inhibitors (HDAC) inhibitors, Janus Kinase 3(JAK-3) inhibitors, CD4 inhibitors, p38 kinase inhibitors, Dihydrofolate Reductase inhibitors, cyclooxygenase (COX) inhibitors, Chemokine receptor antagonists, Glucocorticoid antagonists, Dihydroorotate dehydrogenase(DHODH) inhibitors, and combination therapies.
Vidofludimus is a novel oral inhibitor of dihydroorotate dehydrogenase (DHODH) and of pro-inflammatory cytokine release including interleukin-17 (IL-17A and IL-17F) as well as interferon-gamma which is in Phase IIb development for rheumatoid arthritis and has completed a positive Phase IIa study in inflammatory bowel disease.

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