SE-207499 (ARIFLO), A POTENT AND SELECTIVE 2ND-GENERATION PHOSPHODIESTERASE-4 INHIBITOR - IN-VITRO ANTIINFLAMMATORY ACTIONS

First-generation phosphodiesterase 4 (PDE4) inhibitors, such as rolipr am, inhibit the activation of immune and inflammatory cells. The clini cal use of these compounds is limited by gastrointestinal side effects , such as increased acid secretion and nausea. Consequently, the chall enge has been to design novel PDE4 inhibitors that maintain the anti-i nflammatory actions of rolipram while achieving an improved side effec t profile, Among the first of this new class of PDE4 inhibitors specif ically designed to have an improved therapeutic index relative to earl ier compounds is SB 207499 (Ariflo) tyloxy-4-methoxy-phenyl)-r-1-cyclo hexanecarboxylic acid]. In this study, we compared the anti-inflammato ry and gastric secretogogue activities of SB 207499 with those of roli pram. The cellular models used were (1) histamine release from human b asophils, (2) tumor necrosis factor-alpha generation in human monocyte s, (3) degranulation of human neutrophils, (4) antigen-driven prolifer ation and cytokine synthesis from human T cells and (5) acid secretion from isolated rabbit gastric glands. SB 207499 inhibited the activati on of a variety of immune and inflammatory cells in a concentration-de pendent manner: (1) histamine release in basophils [-log IC25 = 6.6 +/ - 0.3 vs. 8.0 for (R)-rolipram], (2) lipopolysacchride-induced TNF-alp ha formation in monocytes [-log IC50 = 7.0 +/- 0.1 vs. 7.2 +/- 0.1 for (R)-rolipram], (3) fMLP-induced degranulation in neutrophils [-log IC 15 = 7.1 +/- 0.2 vs. 6.4 +/- 0.5 for (R)-rolipram], (4) house dust mit e induced-proliferation of peripheral blood mononuclear cells [-log IC 40 = 6.5 +/- 0.3 vs. 6.4 +/- 0.3 for (R)-rolipram] and (5) ragweed-ind uced production of interferon-gamma [-log IC50 = 5.4] and interleukin- 5 [-log IC50 = 5.0]. Although SB 207499 inhibits the activation of a v ariety of immune and inflammatory cells with a potency equal to that o f 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)-ro lipram]. 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.