4198 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 22
Communications to the Editor
Ta ble 3. Percent Inhibition of TNF-R Release from Fasted
BALB/cJ Mice Stimulated with 20 µg (∼1 mg/kg) of LPS (n )
5/group/experiment)
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most potent compound in the PBMC assay, 9, inhibited
by only 11% at 10 mg/kg. It appears that the larger,
more lipophilic alkoxy groups are a detriment to in vivo
activity, and this could be related to the bioavailability
of these compounds. In two separate experiments, 1 was
given orally (25 mg/kg) to male Lewis rats (n ) 5/group/
experiment) which were then injected with LPS. It was
determined that 1 inhibited TNF-R production by 97 (
1%. Finally, in two separate experiments, the effect of
1 was tested in the adjuvant-induced arthritis model.
Male Lewis rats (n ) 10/group/experiment) were dosed
once daily with 50 mg/kg 1, starting on the day of
injection with adjuvant. Swelling in the rear paws was
reduced by 50 ( 2% in the two experiments (p < 0.001
in each experiment). Similar results have been reported
for 4 in the same model.10
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Con clu sion . We have shown 1 to be a potent inhibi-
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tial phase I compound.
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Su p p or tin g In for m a tion Ava ila ble: Synthetic and bio-
logical procedures and characterization for all compounds (7
pages). Ordering information is given on any current masthead
page.
J M980497B