JTP-27536 [(+)-1,3-Dihydroxy-2-hydroxymethylpropyl-2-ammonium 2-[(R)-3-Cyclo-hexyl-1-phenylpropyl]-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylate Monohydrate],a Novel Inhibitor of Immunoglobulins and lnterleukin-5 with Anti-Inflammatory Properties

摘要

We report a novel synthetic compound JTP-27536 [(+)-1,3-dihydroxy-2-hydroxymethylpropyl-2-ammonium 2-[(R)-3-cyclohexyl-1-phenylpropyl]-1,3-dioxo-2,3-dihydro-1H-isoin-dole-5-carboxylate monohydrate] as an inhibitor of immunoglobulins(Igs)and interleukin(IL)-5 production in vitro and in vivo.JTP-27536 inhibited IgE production in mouse and human B cells with IC_(50)values of 2.5 and 2.1muM,respectively,and the inhibition was stronger than that on lgG1 and IgM production(IC_(50)> 10 muM).JTP-27536 also inhibited IL-5 production in mouse splenocytes and human peripheral blood mononuclear cells with IC_(50)values of 3.3 and 1.3 muM,respectively,without affecting mouse interferon(IFN)-ganna,IL-2,IL-4,IL-10,or human IL-4 production.In contrast,prednisolone not only inhibited mouse IgE production but also mouse IFN-ganna,IL-2,IL-4,and IL-10 and human IL-4 and IL-5 production in vitro.The effect of suplatast tosilate,a Th2 cytokine inhibitor,on antibody and cytokine production was less potent than that of JTP-27536.In vivo animal experiments using dinitrophenylated ascaris-sensitized mice and 2,4,6-trinitro-1-chrolobenzene-induced chronic dermatitis mice showed that JTP-27536 was more potent than suplatast tosilate and comparable with prednisolone in inhibiting ear swelling,antigen-specific IgE and IL-5 production,and cell infiltrations into the inflamed tissue.These results indicate that JTP-27536 is an inhibitor of Igs,in particular IgE,and of IL-5,which has antiallergic properties in mouse dermatitis model,and suggest that an inhibitor of Igs and IL-5 like JTP-27536 may be useful as a drug for the treatment of allergic diseases.