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INFLAMMATION AND IMMUNOPHARMACOLOGY

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 Interleukin-5 with Anti-Inflammatory Properties in Mouse Allergic Dermatitis Model

Japan Tobacco Inc., Central Pharmaceutical Research Institute, Takatsuki, Osaka, Japan

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-isoindole-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 IC₅₀ values of 2.5 and 2.1 µM, respectively, and the inhibition was stronger than that on IgG1 and IgM production (IC₅₀ > 10 µM). JTP-27536 also inhibited IL-5 production in mouse splenocytes and human peripheral blood mononuclear cells with IC₅₀ values of 3.3 and 1.3 µM, respectively, without affecting mouse interferon (IFN)-, IL-2, IL-4, IL-10, or human IL-4 production. In contrast, prednisolone not only inhibited mouse IgE production but also mouse IFN-, 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.

Address correspondence to: Takayuki Mimura, Japan Tobacco Inc., Central Pharmaceutical Research Institute, 1-1 Murasaki-Cho, Takatsuki, Osaka 569-1125, Japan. E-mail: takayuki.mimura{at}ims.jti.co.jp