Neuroprotective polyphenol analogs

A compound, optional technology, applied in the fields of preventing and alleviating neurodegenerative disorders, treating, preventing and alleviating diabetes and Huntington's disease, capable of solving problems of low lipophilicity, poor bioavailability, complexity, etc.

Inactive Publication Date: 2014-07-16
SALK INST FOR BIOLOGICAL STUDIES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although fisetin has been shown to be effective in the rabbit small clot embolism model of stroke (Maher, et al., Brain Research. (2007) 1173, 117-125), its relatively high EC50 in cell-based assays (2 -5μM) and low lipophilicity (CLogP1.24), high tPSA More hydrogen bond donors (HBD=5) and poor bioavailability (Shia, et al., J. Agric. Food Chem. (2009) 57(1), 83-89) suggest that if fisetin is used therapeutically to treat neurological disorders such as stroke, there is room for improvement in medicinal chemistry
However, given its ability to activate multiple target pathways involved in neuroprotection, screening for improvement is significantly more complex than the classical approach currently used to develop single-target drugs

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0467] Example 1 - Chlorogenic Acid Improves Neurological Performance After Embolic Stroke in Rabbits

[0468] After a bolus of vehicle or chlorogenic acid was administered intravenously over 1 minute, embolization was initiated for 5 minutes using a suspension of small-sized clots. In this series of studies, CGA was given at 50 mg / kg [65]. Behavioral analyzes were performed 24 hours after treatment, which allowed the construction of quantitative dose-response curves. Figure 1 shows a graphical representation of the raw data superimposed with the theoretical quantitative analysis curves. For overlaid plots, normal animals are plotted at 0% of the y-axis and abnormal animals are plotted at 100%. The figure shows a positive correlation between the data (circles or triangles) and the statistically fitted quantity curve. In addition, compared with the vehicle control, CGA made P 50 Value increased (abnormal clot volume produced in 50% of treatment groups). For a detailed di...

Embodiment 2

[0469] Example 2 - Fisetin is neuroprotective in vitro and in vivo

[0470]For these studies, cultured HT22 mouse hippocampal cells were used in an in vitro stroke assay [80]. HT22 cells were treated with iodoacetic acid (IAA, an irreversible inhibitor of glyceraldehyde 3-phosphate dehydrogenase (G3PDH)) alone or in the presence of different concentrations of fisetin for 2 h. G3PDH is an enzyme of the glycolytic pathway that catalyzes the synthesis of 1,3 diphosphoglycerate, a "high energy" intermediate for the synthesis of ATP. Cell viability was measured using the standard colorimetric MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay for cell viability. MTT is a pale yellow substrate that is cleaved by living cells to yield a dark blue formazan product. Active mitochondria are required for this process, and even cells that have just died cannot cleave significant amounts of MTT. The graph (FIG. 3) shows that fisetin has a dose-dependent effect on...

Embodiment 3-12-L

[0474] The neuroprotective effect of embodiment 3-12-LOX inhibitor baicalein in vitro

[0475] In Figure 5, panels A-D show that baicalein was able to inhibit neuronal cell death in four additional neurotoxicity paradigms. These include trophic factor withdrawal (TFW), excitotoxicity, glucose starvation and most importantly in chemical ischemia models. Baicalein significantly enhanced the survival of freshly plated, low-density cultured rat cortical neurons in serum-containing media—a trophic factor withdrawal test [92] (Fig. 5A). Using a published excitotoxicity assay [53], baicalein rescued about 35% of the cells (Fig. 5B).

[0476] Baicalein was also neuroprotective in a glucose starvation assay [93], and these results were reproduced using PC12 cells. When these cells were starved of glucose, there was about 70% maximal survival in the presence of NGF. Baicalein increased the survival rate by more than 80% (Fig. 5C). Finally, baicalein prevented cell death in the che...

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Abstract

The present invention provides neuroprotective polyphenol compounds, which can be synthetic analogs of fisetin, baicalein or chlorogenic acid, that maintain neuroprotective, anti-inflammatory, glutathione promoting, and / or antioxidant properties. The neuroprotective polyphenol compounds are useful for promoting, enhancing and / or increasing neuron protection, growth and / or regeneration. The polyphenol compounds further find use for increasing and or maintaining intracellular glutathione (GSH) levels. The polyphenol compounds are also useful for treating, preventing, mitigating and / or delaying neurodegenerative conditions, including diabetes, Parkinson's disease, Huntington's disease, Alzheimer's disease, non-Alzherimer's dementias, multiple sclerosis, traumatic brain injury, spinal cord injury or ALS.

Description

[0001] statement of government support [0002] This invention was made with government support under Grant No. 1U01NS060685 awarded by the National Institute of Neurological Disorders and Stroke (National Institutes of Health). The US Government has certain rights in this invention. [0003] Cross references to related patent applications [0004] This application claims priority to US Provisional Application Serial No. 61 / 522,878, filed August 12, 2011, the disclosure of which is incorporated herein by reference in its entirety. technical field [0005] The present invention provides compounds having neuroprotective, neurotrophic, anti-inflammatory and / or antioxidant properties. The compounds are useful for promoting, enhancing and / or increasing neuronal protection, growth and / or regeneration. The compounds have also been found to be useful for increasing, enhancing and / or maintaining intracellular glutathione (GSH) levels. The present invention also relates to methods f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A01N37/10
CPCA61K31/12A61K31/352A61K31/353A61K31/4025A61K31/47A61K31/4709A61K45/06A61P3/10A61P25/00A61P25/14A61P25/16A61P25/28A61P43/00C07C49/835C07C49/84C07D215/233C07D295/112C07D311/30C07D311/78C07D311/60C07D311/62
Inventor D·R·舒伯特P·A·马赫C·切鲁塔
Owner SALK INST FOR BIOLOGICAL STUDIES
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