Anti-Inflammatory Effects of a Novel Nuclear Factor–κ B Inhibitory Derivative Derived from Pyrazolo[3,4-d]Pyrimidine in Three Inflammation Models

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Abstract
Nuclear factor-κB (NF-κB) plays a central role in inflammatory responses, while its physiological functions are essential for cell survival and proliferation. Currently, drugs targeting NF-κB inhibition have not yet been applied in clinical practice. We investigated the physiological effect of a novel NF-kB inhibitory compound, 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivative (INH #1) on three inflammatory animal models. The pharmacokinetics was measured by LC-MS/MS analysis. Acute hepatitis was induced by administrating LPS and D-(+)-galactosamine hydrochloride followed by the analysis of survival time and inflammatory mediators. Collagen-induced arthritis (CIA) was induced by immunization with type II collagen (CII), and serum-transfer arthritis (STA) was caused by injecting K/BxN mice serum. Clinical and histological scores were evaluated in both arthritis models. Immune cell subset analysis, CII-induced IFN-γ production and proliferation, and measurement of anti-CII IgG antibodies were performed in the CIA model. In the acute hepatitis model, INH #1 suppressed TNF-α production and prevented early death in a dose-dependent manner. INH #1 significantly attenuated arthritis scores and joint inflammation in both arthritis models. Additionally, in the CIA model, dendritic cells in the regional lymph nodes were decreased in the treated mice, and antigen-induced IFN-γ production and cell proliferation in splenocytes were inhibited, while the titers of anti-CII IgG antibodies were comparable regardless of the treatment. Here, we revealed that INH #1 exerted anti-inflammatory effects in vivo via inhibition of inflammatory mediators and suppression of cellular immune responses. This compound could be a novel candidate for inhibition of NF-κB in certain inflammatory diseases. Significance Statement A novel NF-κB inhibitory compound, 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivative (INH #1) that retains physiologically essential NF-κB bioactivity, suppressed inflammation in three different mouse models; the acute hepatitis model, the collagen-induced arthritis model, and the K/BxN serum-transfer arthritis model. These results suggest that this compound could be a novel and potent anti-inflammatory agent.

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