Discovery of a 3-Amino-6-phenyl-pyridazine Derivative as a New Synthetic Antineuroinflammatory Compound

Mirzoeva, Salida; Sawkar, Anu R.; Zasadzki, Magdalena; Guo, Ling; Velentza, Anastasia; Dunlap, Vincent; Bourguignon, Jean‐Jacques; Ramström, Helena; Haiech, Jacques; Eldik, Linda J. Van; Watterson, D. Martin

doi:10.1021/jm015573g

Cited by 58 publications

(60 citation statements)

References 17 publications

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“…The results using multiple endpoints of hippocampal neuronal status are consistent with each other and demonstrate in this mouse model that human A␤ infusion results in neuronal loss and intraperitoneal treatment with MW01-070C provides neuroprotection. This in vivo protection against neuronal damage afforded by MW01-070C treatment is consistent with its established activity as a selective inhibitor of neurotoxic glial products [17].…”

Section: Attenuation Of Neuronal Loss By In Vivo Treatment With a Selsupporting

confidence: 80%

“…2D). This selective in vivo effect of MW01-070C is consistent with its lack of effect on COX-2 levels in cultured cells [17].…”

Section: Selective Suppression Of Neuroinflammatory Mediators By Aminsupporting

confidence: 70%

“…, was synthesized and characterized as previously described [17]. MW01-026Z, 11-(5,6-dihydro-3-iminobenzo-[h]cinnolin-2(3H)-yl)-N-(6-phenylpyridazin-3-yl)undecanamide, is a structural analog of MW01-070C and was synthesized and characterized as previously described [33].…”

Section: Aβ Infusion Into the Cns And Treatment With Inhibitor By Intmentioning

confidence: 99%

“…The discovery rationale was to find safe compounds capable of suppressing pathways that are quantitatively important in proinflammatory and oxidative stress responses of activated glia, versus a primary focus on suppression of peripheral tissue responses. The initial screen with a high throughput, cell-based assay included comparison to extant anti-inflammatory drugs in order to find new synthetic compounds with significantly better, concentration-dependent activity for inhibition of activated glia responses [16,17,35]. A secondary cell-based screen was employed to retain only those compounds that worked via mechanisms distinct from currently available NSAIDs that target COX-2 or p38 MAPK, and to find compounds that would not suppress potential anti-inflammatory responses of glia, such as increased ApoE production in response to A␤1-42 stimulation.…”

Section: Introductionmentioning

confidence: 99%

“…This cell-based, hierarchical approach held the potential of finding safe compounds that would effectively suppress disease-relevant endpoints in glia, but would not suppress the immune response in peripheral tissues, which are needed for responses to infections. MW01-070C fulfills the above criteria based on cell-based activity analyses and initial toxicology studies [17,35]. However, MW01-070C has not been validated in vivo using an animal model of AD-relevant neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

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Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Craft

Watterson

Frautschy

et al. 2004

Neurobiology of Aging

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The critical role of chronic inflammation in disease progression continues to be increasingly appreciated across multiple disease areas, especially in neurodegenerative disorders such as Alzheimer's disease. We report that late intervention with a recently discovered aminopyridazine suppressor of glial activation, developed to inhibit both oxidative and inflammatory cytokine pathways, attenuates human amyloid beta (A␤)-induced glial activation in a murine model. Peripheral administration of the aminopyridazine MW01-070C, beginning 3 weeks after the start of intracerebroventricular infusion of human A␤1-42, decreased the number of activated astrocytes and microglia and the levels of proinflammatory cytokines interleukin-1␤, tumor necrosis factor-␣ and S100B in the hippocampus. 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. The results from this in vivo chemical biology approach provide a proof of concept that targeting of key glia inflammatory cytokine pathways can suppress A␤-induced neuroinflammation in vivo, with resultant attenuation of neuronal damage.

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Section: Attenuation Of Neuronal Loss By In Vivo Treatment With a Selsupporting

confidence: 80%

“…2D). This selective in vivo effect of MW01-070C is consistent with its lack of effect on COX-2 levels in cultured cells [17].…”

Section: Selective Suppression Of Neuroinflammatory Mediators By Aminsupporting

confidence: 70%

Section: Aβ Infusion Into the Cns And Treatment With Inhibitor By Intmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Craft

Watterson

Frautschy

et al. 2004

Neurobiology of Aging

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Construction of 6‐Aminopyridazine Derivatives by the Reaction of Malononitrile with Dichloro‐Substituted Diazadienes

2020

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Enhanced susceptibility of S‐100B transgenic mice to neuroinflammation and neuronal dysfunction induced by intracerebroventricular infusion of human β‐amyloid

Craft

Watterson

Marks

et al. 2005

Glia

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S-100B is an astrocyte-derived protein that is increased in focal areas of the brain most severely affected by neuropathological changes in Alzheimer's disease (AD). Cell-based and clinical studies have implicated S-100B in progression of a pathologic, glial-mediated pro-inflammatory state in the CNS. However, the relationship between S-100B levels and susceptibility to AD-relevant neuroinflammation and neuronal dysfunction in vivo has not been determined. To test the hypothesis that overexpression of S-100B increases vulnerability to beta-amyloid (Abeta)-induced damage, we used S-100B-overexpressing transgenic (Tg) and S-100B knockout (KO) mice in a mouse model that involves intracerebroventricular infusion of human oligomeric Abeta1-42. This model mimics many features of AD, including robust neuroinflammation, Abeta plaques, synaptic damage and neuronal loss in the hippocampus. S-100B Tg, KO, and wild-type (WT) mice were infused with Abeta for 28 days, sacrificed at 60 days, and hippocampal endpoints analyzed. We found that Tg mice showed increased vulnerability to Abeta-induced neuropathology relative to either WT or KO mice. Specifically, Tg mice exhibited enhanced glial activation and neuroinflammation, increased nitrotyrosine staining (a marker of glial-induced neuronal damage), and more pronounced loss of synaptic markers. Interestingly, Tg mice showed no significant differences in Abeta plaque burden compared with WT or KO mice, suggesting that, as in the human situation, the severity of neuronal dysfunction did not correlate with amyloid deposition. Our data are consistent with a model in which S-100B overexpression in AD enhances glial activation and leads to an augmented neuroinflammatory process that increases the severity of neuropathologic sequelae.

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Discovery of a 3-Amino-6-phenyl-pyridazine Derivative as a New Synthetic Antineuroinflammatory Compound

Cited by 58 publications

References 17 publications

Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Aminopyridazines inhibit β-amyloid-induced glial activation and neuronal damage in vivo

Construction of 6‐Aminopyridazine Derivatives by the Reaction of Malononitrile with Dichloro‐Substituted Diazadienes

Enhanced susceptibility of S‐100B transgenic mice to neuroinflammation and neuronal dysfunction induced by intracerebroventricular infusion of human β‐amyloid

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