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Figure 3. Protection by 5k of mice from LPS-induced shock.22
Conclusion
Optimization of the lead compound 1 having modest
dual cytokine regulatory activity but showing CNS
receptor binding anities led to a potent dual cytokine
regulator 5k without showing any signi®cant anities
for the receptors.24 The compound 5k dose-dependently
regulated both TNF-a and IL-10 production in LPS-
stimulated mice. Furthermore, 5k demonstrated potent
protective eects against the lethal challenge of LPS in
mice, suggesting that 5k would be a promising drug can-
didate for the treatment of TNF-a associated diseases
including septic shock.
16. Compounds 5a±k and 7a±c gave satisfactory analytical and
spectroscopic data in accord with their assigned structures.
17. Estrada, A.; Van Kessel, A.; Yun, C. H.; Li, B. Immuno-
pharmacology and Immunotoxicology 1998, 20, 217.
18. In control mice, TNF-a plasma concentration reached
maximum 90 min after LPS injection while IL-10 plasma con-
centration reached maximum within the range of 90±120 min
after LPS injection. Our preliminary examination using anti
IL-10 antibody showed that both TNF-a and IL-10 may be
independently regulated since pretreatment of mice with anti
IL-10 antibody did not aect the degree of TNF-a suppression
by active compounds in LPS-injected mice.
Acknowledgements
We are grateful to Dr. Takashi Horikawa for pharma-
cokinetic studies.
References and Notes
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azine and (4-bromobutyl)benzene synthesized starting from
commercially available (4-hydroxybutyl)benzene.
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21. Analytical and spectroscopic data for 5k: mp 94±95 ꢀC; 1H
NMR (270 MHz, CDCl3) d 2.02 (s, 3H), 2.61 (dd, J=5.3, 4.6