Abstract

First-generation phosphodiesterase 4 (PDE4) inhibitors, such as rolipram, inhibit the activation of immune and inflammatory cells. The clinical use of these compounds is limited by gastrointestinal side effects, such as increased acid secretion and nausea. Consequently, the challenge has been to design novel PDE4 inhibitors that maintain the anti-inflammatory actions of rolipram while achieving an improved side effect profile. Among the first of this new class of PDE4 inhibitors specifically designed to have an improved therapeutic index relative to earlier compounds is SB 207499 (Ariflo) [c-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-r-1-cyclohexanecarboxylic acid]. In this study, we compared the anti-inflammatory and gastric secretogogue activities of SB 207499 with those of rolipram. The cellular models used were (1) histamine release from human basophils, (2) tumor necrosis factor-α generation in human monocytes, (3) degranulation of human neutrophils, (4) antigen-driven proliferation and cytokine synthesis from human T cells and (5) acid secretion from isolated rabbit gastric glands. SB 207499 inhibited the activation of a variety of immune and inflammatory cells in a concentration-dependent manner: (1) histamine release in basophils [−log IC₂₅ = 6.6 ± 0.3 vs. 8.0 for (R)-rolipram], (2) lipopolysacchride-induced TNF-α formation in monocytes [−log IC₅₀ = 7.0 ± 0.1vs. 7.2 ± 0.1 for (R)-rolipram], (3) fMLP-induced degranulation in neutrophils [−log IC₁₅= 7.1 ± 0.2 vs. 6.4 ± 0.5 for (R)-rolipram], (4) house dust mite induced-proliferation of peripheral blood mononuclear cells [−log IC₄₀ = 6.5 ± 0.3 vs. 6.4 ± 0.3 for (R)-rolipram] and (5) ragweed-induced production of interferon-γ [−log IC₅₀ = 5.4] and interleukin-5 [−log IC₅₀ = 5.0]. Although SB 207499 inhibits the activation of a variety of immune and inflammatory cells with a potency equal to that of rolipram, it is >100-fold less potent than the latter compound as an acid secretagogue [−log EC₅₀ = 6.1 ± 0.1 vs. 8.3 ± 0.2 for (R)-rolipram]. Collectively, these data indicate that SB 207499 retains the anti-inflammatory activity of the prototypical PDE4 inhibitor rolipram but is substantially less likely to stimulate gastric acid secretion.