The new class of compounds are aminopyridazines. The original compound, called MW01-070C, is used in an injectable form. More recently developed compounds, such as MW01-2-151WH and MW01-5-188WH, can be taken by mouth.
The compounds were designed and synthesized in the laboratory of D. Martin Watterson, J. G. Searle Professor of Molecular Biology and Biochemistry and professor of molecular pharmacology and biological chemistry, Northwestern University Feinberg School of Medicine, using a synthetic chemistry platform developed by the Northwestern Drug Discovery Program for the rapid discovery of new potential therapeutic targets.
The aminopyridazines are targeted for the potential treatment of certain neurodegenerative diseases that are characterized by neuroinflammation and neuronal loss, such as Alzheimer's disease, Parkinson's disease, stroke and traumatic brain injury. The compounds inhibit over-activation of glia, important cells of the central nervous system that normally help the body mount a response to injury or developmental change but are overactivated in certain neurodegenerative diseases.
The efficacy and safety of the compounds in an Alzheimer's disease animal model was evaluated in collaboration with Linda J. Van Eldik, professor of cell and molecular biology at Feinberg.
The scientists described their Alzheimer's disease drug discovery efforts in recent issues of the Journal of Molecular Neuroscience and the journal Neurobiology of Aging, and a publication that will appear in early 2005 in the journal Current Alzheimer Research. The studies have important implications for future drug development because they provide a proof of concept that targeting neuroinflammation with aminopyridazines is a viable Alzheimer's disease drug discovery approach that has the potential to modulate disease onset and progression, Van Eldik said.
Deposition of the beta-amyloid plaques and neurofibrillary tangles of Alzheimer's disease is associated with glial activation, loss of neurons and decline of cognitive function.
Long-term or excessive activation of glia increases production of chemokines and cytokines, such as interleukin-1 beta (IL-1b), and oxidative stress-related enzymes, such as a highly active form of nitric oxide synthase (iNOS).
The excessive production of the inflammation-related substances can, in turn, contribute to further exacerbation of the disease process.
IL-1b is involved in glial inflammatory and neuronal dysfunction responses, and variants of the IL-1 gene are associated with increased risk for Alzheimer's disease. The iNOS induced as a result of glial activation generates nitric oxide (NO), which can exist in toxic forms that damage neurons.
Therefore, development of new compounds that can modulate these disease-linked biological processes may represent alternative therapeutic approaches and lead to future identification of new drug discovery targets, Van Eldik said.
Van Eldik and co-researchers found that the aminopyridazines inhibited both oxidative and inflammatory cytokine pathways and reduced human amyloid beta (Ab)-induced glial activation in a mouse specially designed to develop many of the hallmarks of Alzheimer's disease pathology, including neuroinflammation, neuronal and synaptic degeneration and amyloid disposition, often called plaques.
Inhibition of neuroinflammation correlated with a decreased neuron loss, restoration towards control levels of synaptic dysfunction biomarkers in the hippocampus and diminished amyloid plaque deposition. Consistent with the pathology changes, treatment with the aminopyridazines also attenuated behavioral deficits in the mice that are due to injury in the part of the brain called the hippocampus, a region that is gradually destroyed in neurodegenerative diseases such as Alzheimer's. The Northwestern investigators are now seeking to raise the funding necessary for testing in humans.
Collaborating with Watterson and Van Eldik on this research were Jeffrey M. Craft, a medical scientist predoctoral student in the Drug Discovery Training Program, and Wenhui Hu and Hantamalala Ranay Ranaivo, postdoctoral scholars in the Drug Discovery Training Program.
This research was supported by grants from the Institute for the Study of Aging; the Alzheimer's Association; and the National Institutes of Health.