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

• Published in: The Journal of pharmacology and experimental therapeutics 1998-11, Vol.287 (2), p.705-711
• Main Authors: Griswold, Don E., Webb, Edward F., Badger, Alison M., Gorycki, Peter D., Levandoski, Patricia A., Barnette, Mary A., Grous, Marilyn, Christensen, Siegfried, Torphy, Theodore J.
• Format: Article
• Language: English
• Subjects: 3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors; Adoptive Transfer; Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclohexanecarboxylic Acids - pharmacology; Humans; Interleukin-4 - antagonists & inhibitors; Interleukin-4 - biosynthesis; Male; Mice; Mice, Inbred Strains; Monocytes; Nitriles; Phosphodiesterase Inhibitors - pharmacology; Pyrrolidinones - pharmacology; Rolipram; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0022-3565
• DOI: 10.1016/S0022-3565(24)37847-4

The ability of the second generation phosphodiesterase 4 inhibitor SB 207499 (Ariflo), [c-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexane carboxylic acid], to inhibit inflammatory cytokine production in vivo was evaluated and compared to that of rolipram, a first generation phosphodiesterase 4 inhibitor. To examine human tumor necrosis factor alpha (TNFα) production, human monocytes were adoptively transferred into Balb/c mice and challenged with lipopolysaccharide (LPS). In this model, SB 207499 inhibited human TNFα production with oral ED50 of 4.9 mg/kg. Similarly, R-rolipram inhibited human TNFα production with an ED50of 5.1 mg/kg, p.o. In contrast to their equipotent activity against TNFα production, SB 207499 (ED50 = 2.3 mg/kg, p.o.) was 10-fold less potent than R-rolipram (ED50 = 0.23 mg/kg, p.o.) in reversing reserpine-induced hypothermia, a model of antidepressant activity. In time course studies, SB 207499 (30 mg/kg, p.o.) inhibited TNFα production for at least 10 hr; substantial plasma concentrations of SB 207499 were detected over the same interval. The ability of SB 207499 to modulate interleukin-4 production in vivo was assessed in a chronic oxazolone-induced contact sensitivity model in Balb/c mice. In this model, topical administration of SB 207499 (1000 μg) inhibited intralesional concentrations of interleukin-4 (55%; P < .01). The results demonstrate that SB 207499 is a potent inhibitor of inflammatory cytokine production in a variety of settings in vivo. Moreover, although it is as potent as R-rolipram in inhibiting TNFα production, it has substantially less central nervous system activity. Thus SB 207499 represents an excellent candidate with which to evaluate the antiinflammatory potential of PDE4 inhibitors.