Disease relevance of A771726

• The rank order of potency of A77 1726 and its analogues in binding or enzyme inhibition was similar to that for inhibition of the mouse delayed type hypersensitivity response [1].
• A77 1726 induces differentiation of human myeloid leukemia K562 cells by depletion of intracellular CTP pools [2].
• METHODS AND RESULTS: Plaque assay of virus yield from endothelial or Vero cells after inoculation with each of four clinical HSV-1 isolates demonstrated a dose-dependent reduction of virus production in the presence of pharmacologic concentrations of A77 1726, the active metabolite of leflunomide [3].
• Addition of either one of three different inhibitors of NFkappaB (SN50, PDTC, and A771726) to mouse TNF-alpha sensitized WEG-1 cells to the toxicity of the cytokine [4].
• Accordingly to results obtained with primary astrocytes, both A77 1726 and PD98059 significantly reduced IFN-gamma+LPS-induced NO synthesis in the cultures of rat astrocytoma cell line C6 [5].

High impact information on A771726

• METHODS: Effects of pharmacologic concentrations of teriflunomide on CD3/CD28- and lymphocyte function-associated antigen 1-induced signal transduction and activation of primary human T cells were investigated [6].
• Moreover, teriflunomide abolished molecule relocalization to the IS and induction of T cell/APC conjugates [6].
• RESULTS: Teriflunomide inhibited T cell receptor (TCR)/CD3-mediated calcium mobilization, but other critical T cell signaling events, including activation of MAPK and NF-kappaB, remained unaltered [6].
• Five potent inhibitors of mammalian DHODH, Redoxal, dichloroallyl lawsone (DCL), and three analogs of A77 1726 were tested as inhibitors of the malarial enzyme [7].
• Furthermore, A77 1726 suppresses tyrosine kinases involved in signal transduction pathways [8].

Chemical compound and disease context of A771726

• The relative lack of toxicity of A77 1726 on nonlymphoid cells may be due to the ability of these cells to fulfill their ribonucleotide requirements by use of salvage pyrimidine pathway, which makes them less dependent on de novo synthesis [9].

Biological context of A771726

• Dihydroorotate dehydrogenase is a high affinity binding protein for A77 1726 and mediator of a range of biological effects of the immunomodulatory compound [1].
• Tyrosine phosphorylation of the beta-chain of the IL-2R, which is required for IL-2-driven proliferation, is also inhibited by A77 1726 [10].
• Incubation of peripheral blood neutrophils from healthy controls with A77 1726 confirmed the inhibitory effect on chemotaxis [11].
• Multiple inhibition experiments indicate that PQC (and thus brequinar) and A77 1726 have overlapping binding sites [12].
• A77 1726 also inhibited p56lck activity in LSTRA membrane preparation and immunoprecipitates; the IC50 values for inhibition of immunoprecipitated p56lck autophosphorylation and exogenous substrate histone 2B were 80 and 40 microM, respectively [13].

Anatomical context of A771726

• Here murine CTLL cell lines were studied to determine which of the biochemical targets of A77 1726 was responsible for the observed inhibition of proliferation and cytotoxic activity [10].
• The T-cell receptor-mediated in vitro activatability of a P2-specific T-cell hybridoma was diminished by high concentrations of A77 1726, as evidenced by reduced Ca(2+) flux into the cytosol [8].
• The human high-affinity binding protein for radiolabelled A77 1726 was purified from solubilized U937 membranes by following the binding activity through the purification process and was characterized as the mitochondrial enzyme dihydro-orotate dehydrogenase (DHO-DH) [14].
• A77 1726 suppressed the production of SAA in human hepatocytes activated by IL-1beta in a dose-dependent manner (0-50 microM) [15].
• The extracellular concentration of TNFalpha was found to be significantly decreased in media containing cultured macrophages at 24 hours for all tested doses of A77 1726 [16].

Associations of A771726 with other chemical compounds

• The in vitro effects of A77 1726, the active metabolite of leflunomide, and methotrexate on peripheral blood neutrophils from 7 healthy control subjects were also investigated [11].
• CONCLUSION: These studies reveal that the blood levels of A77 1726 in Lewis rats satisfy in vitro requirements for both inhibition of de novo pyrimidine synthesis and protein tyrosine kinase activity [17].
• The in vivo properties of A771726 are reminiscent of another immunosuppressive agent, brequinar sodium, which has been shown to be a nonomolar inhibitor (Ki = 10-30 nM) of the enzyme dihydroorotate dehydrogenase (DHODase) [18].
• This kinetic data suggests that recent crystal structures of human DHODH complexed with orotate and A77 1726 or brequinar may not represent the relevant physiological binding sites for these inhibitors [Liu, S., Neidhardt, E. A., Grossman, T. H., Ocain, T., and Clardy J. (2000) Structure 8, 25-33] [12].
• To determine the ability of acute topical treatment with leflunomide to inhibit mast cell degranulation, three groups of five animals received either vehicle, 100 microg A77 1726, or 1000 g A77 1726 60 min prior to aerosol allergen challenge [19].

Gene context of A771726

• Thus the inhibition of DHODH by A77 1726 prevents lymphocytes from accumulating sufficient pyrimidines to support DNA synthesis [20].
• Human hepatocytes, treated or not treated with A77 1726, were stimulated with IL-1beta and the cellular lysates were analysed by immunoblot using anti-phospho-specific mitogen-activated protein kinase (MAPK) and IkappaB-alpha [15].
• METHODS: Human synoviocytes were stimulated with IL-1alpha or tumour necrosis factor alpha (TNF-alpha) in the presence of A77 1726 [21].
• A77 1726 inhibited IL-1beta-induced p38 and c-Jun N-terminal kinase 1/2 (JNK1/2) activation, whereas A77 1726 did not affect IL-1beta-induced NF-kappaB activation in hepatocytes [15].
• In contrast, MMP-1 and IL-6 production was inhibited at high A77 1726 concentrations (> 10 microM), whereas TIMP-1 was not affected [21].

Analytical, diagnostic and therapeutic context of A771726

• BACKGROUND: FK778, a derivative of the active leflunomide-metabolite, A77 1726, has been shown to be a powerful immunosuppressant in several transplantation models, particularly efficient in the prevention of chronic allograft rejection [22].
• Therapeutic drug monitoring of A77 1726 may be useful in predicting the efficacy of leflunomide treatment [23].
• Effects of leflunomide were evaluated by two treatment protocols: mice treated with MLD-SZ were injected intraperitoneally with A77 1726 for 10 consecutive days, either during the first 10 days of the disease (early treatment), or starting from day 10 after disease induction (late treatment) [24].
• A rapid and simple determination of A77 1726 in human serum by high-performance liquid chromatography and its application for optimization of leflunomide therapy [25].
• This study was conducted to investigate the importance of direct contact between Kupffer cells (KCs) and hepatocytes (HCs) during the hepatic inflammatory responses, and the effect of leflunomide's active metabolite, A771726, on cytokines in KCs and HCs (DC cocultures) and KC cultures using an in vitro approach [26].

References