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

Abstract

We report a novel synthetic compound JTP-27536 [(ϩ)-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 IC 50 values of 2.5 and 2.1 M, respectively, and the inhibition was stronger than that on IgG1 and IgM production (IC 50 Ͼ 10 M). 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 M, 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 ascarissensitized 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.

Pinus densiflora bark extract ameliorates 2,4‐dinitrochlorobenzene‐induced atopic dermatitis in NC/Nga mice by regulating Th1/Th2 balance and skin barrier function

“…Administration of PBE (12.5, 25, and 50 mg/kg) dose‐dependently decreased in levels of IgE (32%, 42%, and 51%, respectively) and IgG 1 (32%, 47%, and 56%, respectively), whereas serum IgG 2a level was not decreased by PBE. Previous study indicated that PD inhibits IgE, IgG 1 , and IgG 2a in mice (Mimura, Shinozaki, Kawasaki, & Iwamura, ). The PD group showed suppressed serum IgE, IgG 1 , and IgG 2a levels compared with the control group (40%, 50%, and 58%, respectively).…”

“…In contrast, PD inhibited not only splenic production of Th2 cytokines and serum level of IgG 1 but also splenic production of IFN‐γ and serum level of IgG 2a . The inhibitory effects of PD were also observed in mouse allergic dermatitis model (Mimura et al, ). These results show that PBE on IgG 2a /IgG 1 ratio appeared to be more effective rather than PD.…”

Effects of Triterpenoid-Rich Extracts of <i>Ganoderma tsugae</i> on Airway Hyperreactivity and Th2 Responses in vivo

“…Prednisolone treatment is known to decrease AHR, eosinophilia in the lung, serum IgE levels, and IL-2 and IL-4 production by ConA-stimulated splenocytes [38, 39]. However, the side effects of corticosteroids may cause problems.…”

Postelicitation model of allergic contact dermatitis for predicting the efficacy of topical drugs

“…Others have reported ear swelling responses that were as excessive as 1800 μ m (20). Recently, experimental drugs, such as CX‐659S (16,17), JTP‐27536 (21) and olopatidine‐HCl (15,20) were tested in related chronic inflammation models with contact sensitizers that induced excessive ear swellings larger than 150 μ m. Unless specially required, such as in itch models (22), we conclude that the determination of anti‐inflammatory effects of test compounds does not require excessive ear swellings over 150 μ m.…”