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.
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 microM, respectively, and the inhibition was stronger than that on IgG1 and IgM production (IC50 > 10 microM). 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 microM, respectively, without affecting mouse interferon (IFN)-gamma, IL-2, IL-4, IL-10, or human IL-4 production. In contrast, prednisolone not only inhibited mouse IgE production but also mouse IFN-gamma, 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.
Mimura
Takayuki
T
Japan Tobacco Inc., Central Pharmaceutical Research Institute, 1-1 Murasaki-Cho, Takatsuki, Osaka 569-1125, Japan. takayuki.mimura@ims.jti.co.jp
Shinozaki
Yuichi
Y
Kawasaki
Hisashi
H
Iwamura
Hiroyuki
H
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D000917:Antibody Formation / Q000187:drug effects; D000918:Antibody Specificity; D001200:Ascaris / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects; D002908:Chronic Disease; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D017449:Dermatitis, Allergic Contact / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007073:Immunoglobulin E / Q000187:drug effects; D007136:Immunoglobulins / Q000187:drug effects*; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D015848:Interleukin-5 / Q000037:antagonists & inhibitors*; D054833:Isoindoles; D051379:Mice; D008807:Mice, Inbred BALB C; D010853:Picryl Chloride; D011239:Prednisolone / Q000494:pharmacology; D013154:Spleen / Q000166:cytology
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003510:Cyclohexanes; D007136:Immunoglobulins; D007211:Indoles; D015848:Interleukin-5; D054833:Isoindoles; C503118:1,3-dihydroxy-2-hydroxymethylpropyl-2-ammonium 2-((R)-3-cyclo-hexyl-1-phenylpropyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylate monohydrate; D007073:Immunoglobulin E; D011239:Prednisolone; D010853:Picryl Chloride