title: Leflunomide metabolite analogue alpha-cyano-beta-hydroxy-beta-methyl-N-[3-(trifluoromethyl)phenyl]propenamide inhibits IgE/FcepsilonRI receptor-mediated mast cell leukotriene release and allergic asthma in mice.
abstract: Mast cell-derived leukotrienes (LTs) play a critical role in the pathophysiology of allergy and asthma. We synthesized 13 analogues of leflunomide (LFM) and examined their in vitro effects on IgE/FcepsilonRI receptor-mediated mast cell LT release. We observed that the novel LFM analogue, alpha-cyano-beta-hydroxy-beta-methyl-N-[3-(trifluoromethyl) phenyl]propenamide (LFM-A8), is a more potent inhibitor than LFM of IgE/FcepsilonRI receptor-mediated LTC4 release from RBL-2H3 rat mast cells. Notably, LFM-A8 showed promising biologic activity in a mouse model of allergic asthma. Treatment of ovalbumin (OVA)-sensitized mice with LFM-A8 prevented the development of airway hyperresponsiveness to methacholine in a dose-dependent fashion. Furthermore, LFM-A8 inhibited the eosinophil recruitment to the airway lumen after the OVA challenge in a dose-dependent fashion. Therefore further development of compound LFM-A8 may provide the basis for new and effective treatment programs for severe allergic disorders, including allergic asthma.
authors.affiliation: Department of Allergy, Parker Hughes Institute, St. Paul, MN 55113, USA.
authors.forename: R
authors.initials: R
authors.lastname: Malaviya
authors.forename: F M
authors.initials: FM
authors.lastname: Uckun
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D007555:Isoxazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077339:Leflunomide; D017997:Leukotriene C4 / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D017455:Receptors, IgE / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000276:Adjuvants, Immunologic; D007555:Isoxazoles; D017455:Receptors, IgE; D017997:Leukotriene C4; D000077339:Leflunomide