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Vol. 287, Issue 2, 705-711, November 1998
and Interleukin-4
Production in vivo
Departments of
Pulmonary Pharmacology (D.E.G., E.F.W., M.A.B.,
M.G., T.J.T.),
Bone and Cartilage Biology (A.M.B.),
Drug Metabolism and
Pharmacokinetics (P.D.G., P.A.L.) and
Medicinal Chemistry (S.C.),
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania
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 (TNF
) production, human monocytes were adoptively transferred into Balb/c mice and challenged with
lipopolysaccharide (LPS). In this model, SB 207499 inhibited human
TNF production with oral ED50 of 4.9 mg/kg. Similarly,
R-rolipram inhibited human TNF production with an ED50
of 5.1 mg/kg, p.o. In contrast to their equipotent activity against
TNF 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 TNF 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 TNF 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.
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