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Compounds for stabilizing ryanodine receptors from aberrant levels of calcium release

A compound, alkyl technology, applied in the field of compounds used to stabilize ryanodine receptors from abnormal levels of calcium release, can solve problems such as aggravating amyloid disorders, and achieve the effect of reducing amyloid disorders

Active Publication Date: 2015-12-30
ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, difuranine may be pathogenic; long-term oral treatment (10+ months) with difuranine was found to exacerbate amyloid disorders (Zhang et al., 2010, Journal of Neuroscience, 30:8566-8580 )

Method used

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  • Compounds for stabilizing ryanodine receptors from aberrant levels of calcium release
  • Compounds for stabilizing ryanodine receptors from aberrant levels of calcium release
  • Compounds for stabilizing ryanodine receptors from aberrant levels of calcium release

Examples

Experimental program
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Effect test

Embodiment 1

[0154] In some cases, it may be necessary to protect some reactive functionalities in order to achieve some of the transformations described above. In general, the required such protecting groups and the conditions required for attachment or removal of such groups will be apparent to those skilled in the art of organic synthesis. For the trained practitioner, authoritative works describing the many alternatives are: JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 3rd ed., Wiley, New York 1999, " The Peptides"; Volume 3 (eds. E. Gross and J. Meienhofer), Academic Press, London and New York 1981, "Methodender organischen Chemie", Houben-Weyl, 4.sup.thedition, Vol.15 / l, Georg Thieme Verlag, Stuttgart 1974, H.-D . Jakubke and H. Jescheit, "Aminosauren, Peptide, Protein", Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982 and / or Jochen Lehmann, "Chemieder Kohlen...

Embodiment 2

[0161] Example 2: Stabilization of RyR by difuranine

[0162] The procedure set forth in Example 1 was used to investigate whether a RyR stabilizing compound (nifefrazine) could affect neuronal properties related to AD pathogenesis and traumatic brain injury.

[0163] In two AD models (3xTg-AD and PS1 / APP), treatment with nitrofuralin (1-{[5-(4-nitrophenyl)-2-furyl]methyleneamino}imidazolidine -2,4-dione; the trade name for the nanocrystalline formulation of difurynine sodium ) for 4 weeks of sub-chronic treatment (5-10mg / kg, consistent with the clinical dose in the population), the excessive ER-Ca in dendritic spines 2+ Release was restored to NonTg levels (Fig. 1), synaptic transmission properties and synaptic integrity were restored (Fig. 2), and soluble and insoluble Aβ deposition was significantly reduced ( Figure 2E ), and normalized RyR2 expression (Fig. 3). These findings not only support the RyR-Ca 2+ The central role of dysregulation in AD pathogenesis and β-am...

Embodiment 3

[0166] Example 3: Optimization of RyR2-stabilized compounds from shoots to leads (Hit-to-lead)

[0167] Although initially based on the backbone analogs of dinitrofuranne, new and distinct drug-like analogs have been developed that retain strong in vitro activity and exhibit improved pharmaceutical properties (see Image 6 ). Incorporation of substructural features into the difuranine-like scaffold confers improved drug properties, thereby enabling the systematic development of active candidates for AD and other neurodegenerative diseases.

[0168]

[0169] The synthesis of different RyR stabilizers is accomplished by well-established Suzuki chemistry followed by hydrazone formation. 20 different aryl halides and 5 hydrazines were used to generate 100 new candidates. Briefly, under Suzuki reaction conditions in the presence of a base such as cesium carbonate, a catalytic tetrakis(triphenylphosphine)palladium(0) was used with an aryl halide (R 1 ) treatment of 5-formyl-2-...

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Abstract

Disclosed herein are methods and compositions comprising compounds capable of normalizing neuronal calcium dyshomeostasis. Also disclosed are methods comprising these compounds for treating neuronal or neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, fronto-temporal dementia, Pick's disease, chronic traumatic encepholopathy, traumatic brain injury, stroke, cerebellar ataxia, multiple sclerosis, Down syndrome, and aging-related CNS disorders.

Description

Background technique [0001] Effective drug therapies remain elusive for the treatment of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease, frontotemporal dementia, and brain injuries such as Traumatic Brain Injury (TBI) and associated cognitive deficits, CTE (Chronic Traumatic Encephalopathy)). [0002] To date, multicenter phase III clinical trials for the treatment of AD and other neurodegenerative diseases have been unsuccessful, not necessarily because the goal was not met, but that goal may be incompatible with the desired treatment outcome (ie, preservation of cognitive ability ) is irrelevant. Most clinical trials for AD therapy have focused on the manipulation of amyloid precursor protein (APP), and while amyloid levels were reduced in many clinical trials, there was no positive effect on memory performance. In addition, complications such as toxicity problems and deterioration of cognitive function occur (Golde e...

Claims

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Application Information

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IPC IPC(8): A61K31/15A61P25/28
CPCA61K31/341A61K31/4166A61K31/4427A61P9/00A61P25/00A61P25/14A61P25/16A61P25/28A61P43/00C07D307/52C07D307/54C07D405/12C07D407/12
Inventor 格雷斯·E·施图茨曼罗素·达尔克里斯托弗·H·卡伊欧
Owner ROSALIND FRANKLIN UNIVERSITY OF MEDICINE AND SCIENCE
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