TY - JOUR
T1 - Discovery of a New Class of Synthetic Protein Kinase Inhibitors that Suppress Selective Aspects of Glial Activation and Protect Against β-Amyloid Induced Injury
T2 - A Foundation for Future Medicinal Chemistry Efforts Focused on Targeting Alzheimer's Disease Progression
AU - Watterson, D. Martin
AU - Velentza, Anastasia V.
AU - Zasadzki, Magdalena
AU - Craft, Jeffrey M.
AU - Haiech, Jacques
AU - Van Eldik, Linda J.
N1 - Funding Information:
These studies were supported in part by the Institute for the Study of Aging, the Alzheimer’s Association, and NIH grants AG13939 and AG20243. A.V.V. was supported by NIH training grant AG00260.
PY - 2003
Y1 - 2003
N2 - A prevailing hypothesis in Alzheimer's disease (AD) research is that chronically activated glia may contribute to neuronal dysfunction, through generation of a detrimental state of neuroinflammation. This raises the possibility in drug discovery research of targeting the cycle of untoward glial activation and neuronal dysfunction that characterizes neuroinflammation. Success over the past century with effective anti-inflammatory drug development, in which the molecular targets are intracellular enzymes involved in signal transduction events and cellular homeostasis, demands that a similar approach be tried with neuroinflammation. Suggestive clinical correlations between inflammation markers and AD contribute to the urgency in addressing the hypothesis that targeting selective glial activation processes might be a therapeutic approach complementary to existing drugs and discovery efforts. An academic collaboratorium initiated a rapid inhibitor discovery effort 2 yr ago, focused on development of novel compounds with new mechanisms of action in AD-relevant cellular processes, in order to obtain the small-molecule compounds required to address the neuroinflammation hypothesis and provide a proof of concept for future medicinal chemistry efforts. We summarize here our progress toward this goal in which novel pyridazine-based inhibitors of gene-regulating protein kinases have been discovered. Feasibility studies indicate their potential utility in current medicinal chemistry efforts focused on improvement in molecular properties and the longer term targeting of AD-related pathogenic processes.
AB - A prevailing hypothesis in Alzheimer's disease (AD) research is that chronically activated glia may contribute to neuronal dysfunction, through generation of a detrimental state of neuroinflammation. This raises the possibility in drug discovery research of targeting the cycle of untoward glial activation and neuronal dysfunction that characterizes neuroinflammation. Success over the past century with effective anti-inflammatory drug development, in which the molecular targets are intracellular enzymes involved in signal transduction events and cellular homeostasis, demands that a similar approach be tried with neuroinflammation. Suggestive clinical correlations between inflammation markers and AD contribute to the urgency in addressing the hypothesis that targeting selective glial activation processes might be a therapeutic approach complementary to existing drugs and discovery efforts. An academic collaboratorium initiated a rapid inhibitor discovery effort 2 yr ago, focused on development of novel compounds with new mechanisms of action in AD-relevant cellular processes, in order to obtain the small-molecule compounds required to address the neuroinflammation hypothesis and provide a proof of concept for future medicinal chemistry efforts. We summarize here our progress toward this goal in which novel pyridazine-based inhibitors of gene-regulating protein kinases have been discovered. Feasibility studies indicate their potential utility in current medicinal chemistry efforts focused on improvement in molecular properties and the longer term targeting of AD-related pathogenic processes.
KW - Alzheimer's disease
KW - Cytokines
KW - Drug discovery
KW - Glia
KW - Neuroinflammation
KW - Protein kinase inhibitor
KW - Pyridazines
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U2 - 10.1385/JMN:20:3:411
DO - 10.1385/JMN:20:3:411
M3 - Article
C2 - 14501026
AN - SCOPUS:0642309498
SN - 0895-8696
VL - 20
SP - 411
EP - 423
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
IS - 3
ER -