SB 207499 (Ariflo), a Second Generation Phosphodiesterase 4 Inhibitor, Reduces Tumor Necrosis Factor a and Interleukin-4 Production in vivo

The ability of the second generation phosphodiesterase 4 in-hibitor SB 207499 (Ariflo), [c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexane carboxylic acid], to inhibit in-flammatory cytokine production in vivo was evaluated and compared to that of rolipram, a first generation phosphodies-terase 4 inhibitor. To examine human tumor necrosis factor alpha (TNFa) production, human monocytes were adoptively transferred into Balb/c mice and challenged with lipopolysac-charide (LPS). In this model, SB 207499 inhibited human TNFa production with oral ED50 of 4.9 mg/kg. Similarly, R-rolipram inhibited human TNFa production with an ED50 of 5.1 mg/kg, p.o. In contrast to their equipotent activity against TNFa pro-duction, SB 207499 (ED50 5 2.3 mg/kg, p.o.) was 10-fold less potent than R-rolipram (ED50 5 0.23 mg/kg, p.o.) in reversin