SE-207499 (ARIFLO), A 2ND-GENERATION PHOSPHODIESTERASE-4 INHIBITOR, REDUCES TUMOR-NECROSIS-FACTOR-ALPHA AND INTERLEUKIN-4 PRODUCTION IN-VIVO

The ability of the second generation phosphodiesterase 4 inhibitor SE 207499 (Ariflo), (3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexane ca rboxylic acid], to inhibit inflammatory cytokine production in vivo wa s evaluated and compared to that of rolipram, a first generation phosp hodiesterase 4 inhibitor. To examine human tumor necrosis factor alpha (TNF alpha) production, human monocytes were adoptively transferred i nto Balb/c mice and challenged with lipopolysaccharide (LPS). In this model, SE 207499 inhibited human TNF alpha production with oral ED50 o f 4.9 mg/kg. Similarly, R-rolipram inhibited human TNF alpha productio n with an ED,, of 5.1 mg/kg, p.o. In contrast to their equipotent acti vity against TNF alpha production, SE 207499 (ED50 = 2.3 mg/kg, p.o.) was 10-fold less potent than R-rolipram (ED50 = 0.23 mg/kg, p.o.) in r eversing reserpine-induced hypothermia, a model of antidepressant acti vity, in time course studies, SE 207499 (30 mg/kg, p.o.) inhibited TNF alpha production for at least 10 hr; substantial plasma concentration s of SE 207499 were detected over the same interval. The ability of SE 207499 to modulate interleukin-4 production in vivo was assessed in a chronic oxazolone-induced contact sensitivity model in Balb/c mice. I n this model, topical administration of SE 207499 (1000 mu g) inhibite d intralesional concentrations of interleukin-4 (55%; P < .01). The re sults demonstrate that SE 207499 is a potent inhibitor of inflammatory cytokine production in a variety of settings in vivo. Moreover, altho ugh it is as potent as R-rolipram in inhibiting TNF alpha production, it has substantially less central nervous system activity. Thus SE 207 499 represents an excellent candidate with which to evaluate the antii nflammatory potential of PDE4 inhibitors.