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Systemic Lupus Erythematosus
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Maria A. Giraldo-Isaza, Bettina F. Cuneo
Antimetabolite, blocks pyrimidine synthesis by inhibiting the dihydroorotate dehydrogenase. Avoid as no data available and long half-life of its metabolite, teriflunomide, is of concern. Wait 2 years after discontinuation of therapy to attempt conception. Cholestyramine washout is recommended if detectable levels prior to a planned pregnancy or once pregnant to accelerate clearance. This is achieved with a level of <0.02 mg/L documented in 2 occasions 14 days apart. The risk of congenital anomalies does not appear increased in those pregnancies exposed to leflunomide following cholestyramine washout [67].
Immunomodulating Agents in Gastrointestinal Disease
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Samir A. Shah, Athos Bousvaros, A. Christopher Stevens
Like MMF, brequinar sodium (BQR) interferes with DNA synthesis and T and B cell proliferation. It inhibits the enzyme dihydroorotate dehydrogenase, which is essential in the de novo synthesis of pyrimidines in the lymphocyte. Brequinar sodium decreases DNA and ribonucleic acid (RNA) synthesis, lymphocyte proliferation, and cytokine and antibody production. In vivo transplantation experiments in rat and monkey animal models demonstrate that brequinar decreases proinflamma-tory cytokine messenger RNA (mRNA) in allografts and prolongs cardiac and liver allograft survival [189–191].
History of antifungals
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Emily L. Larkin, Ali Abdul Lattif Ali, Kim Swindell
F901318 impedes pyrimidine biosynthesis by inhibiting the fungal enzyme dihydroorotate dehydrogenase [95]. This new antifungal is ineffective against Candida species but is highly active against molds such as Aspergillus, Scedosporium, and Lomentospora, including azole-resistant types [95–97]. Like APX001, humans have their own version of dihydroorotate dehydrogenase, which is not inhibited by F901318, indicating that it will have a low toxicity that has been demonstrated in in vivo models [95]. Clinical trials to evaluate its tolerability and safety have been undertaken.
Newly approved agents for relapsing remitting multiple sclerosis: how real-world evidence compares with randomized clinical trials?
Published in Expert Review of Neurotherapeutics, 2021
Giancarlo Comi, Gloria Dalla Costa, Lucia Moiola
Teriflunomide is an oral immunomodulatory drug approved for the treatment of RRMS by the FDA in 2012 and by EMA in 2013 [62,63]. The drug acts by selectively and reversibly blocking the enzyme dihydroorotate dehydrogenase which ultimately lead to the inhibition of pyrimidine de novo synthesis. Therefore TFL blocks the proliferation of rapidly dividing cells, including activated T and B cells which are though to drive the inflammatory processes in MS [64]. The effects of TFL appear to be cytostatic, not cytotoxic because the cell viability is not affected [65]. Moreover a recent study suggested that TFL also corrects metabolic disturbances in T cells, and may promote recovery of an altered T cell receptor repertoire in autoimmunity [66]. It is administered once-daily, available in 14 mg doses globally and additionally 7 mg doses in the US.
An expert overview of emerging therapies for acute myeloid leukemia: novel small molecules targeting apoptosis, p53, transcriptional regulation and metabolism
Published in Expert Opinion on Investigational Drugs, 2020
Kapil Saxena, Marina Konopleva
The process of tumorigenesis is characterized by abnormal, uncontrolled cell division at a rate that outpaces cell death. Thus, the principal goal of systemic chemotherapy for decades has been to slow down cell division and trigger cell death in actively dividing malignant cells. These therapies may be targeted to specific mutated proteins, such as using tyrosine kinase inhibitors for FLT3-mutated AML. Alternatively, they may be comparatively less specific, causing direct DNA damage primarily in actively dividing cells, a mechanism employed by conventional chemotherapies such as alkylating and intercalating agents. Whether by inhibiting oncoproteins or inducing DNA damage, such therapies typically cause cell death by apoptosis [19,122]. An alternative mechanism for slowing cell division is by depriving cells of necessary building blocks for cell division. This class of anti-metabolite therapies includes agents such as 5-fluorouracil, which reduces cell division by inhibiting thymidylate synthase and reducing cellular stores of deoxythymidine monophosphate (dTMP), a pyrimidine nucleotide necessary for DNA synthesis [123]. It is in the context of targeting AML using anti-metabolites that dihydroorotate dehydrogenase (DHODH) inhibitors were re-introduced into the field of cancer therapeutics.
Fluorinated scaffolds for antimalarial drug discovery
Published in Expert Opinion on Drug Discovery, 2020
Charu Upadhyay, Monika Chaudhary, Ronaldo N. De Oliveira, Aniko Borbas, Prakasha Kempaiah, Poonam S, Brijesh Rathi
Deng, X. and coworkers have provided a detailed analysis of protein-ligand interaction between dihydroorotate dehydrogenase (DHODH) and a series of triazolopyrimidine-based inhibitors [53]. For this class of compounds, PfDHODH was identified as the target with selective and potent antiplasmodial activity [54,55]. It was observed that the increased fluorine content of these compounds leads to enhanced binding affinity with mammalian DHODHs, which is driven by hydrophobic interactions between fluorine and hydrocarbons [56]. Hydrophobic groups such as -CF3 and -SF5 [57,58] at the para position of aniline forms strong interactions in the hydrophobic site of the inhibitor binding pocket contributing high potency and metabolic stability [59]. The substitution of the triazolopyrimidine ring with difluoroethyl or trifluoromethyl moiety at C-12 further improved the activity and metabolic stability.