566 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3
Letters
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In the case of joint inflammation, the p38 MAPK
pathway is quantitatively important and a viable target
for drug discovery, whereas our results raise the pos-
sibility that other kinase-mediated pathways might be
more viable targets for the CNS.
Compound 1 has key features that are attractive in
early-generation compounds. These include its selective
targeting of steps in the glial activation loop that are
disease-linked without perturbation of related path-
ways. In addition, compound 1 does not target the same
regulatory pathways that can be critical in peripheral
inflammatory responses. This raises the possibility that
future refinements of compound 1 structure and activity
might allow avoidance of undesired side effects such as
suppression of peripheral inflammatory responses. Fi-
nally, pyridazines are attractive starting points for
future refinement because they have the potential for
generating chemically diverse compounds as part of in-
parallel syntheses, and slight modifications result in a
range of pharmacological activities.
Con clu sion . Compound 1 is a new glial activation
inhibitor that has desirable functional properties, tar-
gets different pathways compared to currently available
experimental drugs, and is amenable to rapid chemical
diversification with facile chemistries, making it an
attractive starting point for future refinement.
(7) Lukas, T. J .; Mirzoeva, S.; Slomczynska, U.; Watterson, D. M.
Identification of Novel Classes of Protein Kinase Inhibitors
Using Combinatorial Peptide Chemistry Based on Functional
Genomics Knowledge. J . Med. Chem. 1999, 42, 910-919.
(8) Bhagwat, S. S.; Manning, A. M.; Hoekstra, M. F.; Lewis, A. Gene-
regulating protein kinases as important antiinflammatory tar-
gets. Drug Discovery Today 1999, 4, 472-479.
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Mechanisms of Action. J . Clin. Psychiatry 1982, 43, 19-24. (b)
Apter, J . T.; Allen, L. A. Buspirone: Future Directions. J . Clin.
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Ack n ow led gm en t. These studies were supported in
part by NIH Grants AG00260, AG13939, and RR13810
as well as by grants from the Alzheimer’s Association
and the Institute for the Study of Aging. We thank Dr.
Thomas J . Lukas for his assistance and advice. D.M.W.
is the J . G. Searle Professor of Molecular Biology and
Biochemistry.
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Protein Kinase II Inhibitor KN-93 Reduces Dopamine Contents
in PC12h Cells. Biochem. Biophys. Res. Commun. 1991, 181,
968-975.
Su p p or tin g In for m a tion Ava ila ble: Details of experi-
mental procedures for the synthesis of compounds, activity
assays, and analytical characterization data. This material is
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