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Compounds used to stabilize ryanodine receptors against abnormal levels of calcium release

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

Active Publication Date: 2018-06-12
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 pathology (Zhang et al., 2010, Journal of Neuroscience, 30:8566 -8580)

Method used

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  • Compounds used to stabilize ryanodine receptors against abnormal levels of calcium release
  • Compounds used to stabilize ryanodine receptors against abnormal levels of calcium release
  • Compounds used to stabilize ryanodine receptors against abnormal levels of calcium release

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Experimental program
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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 edition, Wiley, New York 1999, "The Peptides"; Volume 3 (eds. E. Gross and J. Meienhofer), Academic Press, London and New York 1981, "Methoden derorganischen Chemie", Houben-Weyl, 4 .sup.th edition, Vol.15 / l, Georg ThiemeVerlag, Stuttgart 1974, H.-D.Jakubke and H.Jescheit, "Aminosauren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982 and / or Jochen Lehmann, "Chemie der K...

Embodiment 2

[0160] Ca 2+ Imaging and Compound Administration. Glass coverslips with 2-AM filled N2a cells were placed in the dipping chamber on the stage of an upright Olympus BX51 microscope (coupled to a 2-photon laser imaging system). To induce RyR-mediated calcium responses, a caffeine bath was applied to N2a cells incubated (30 min) in control medium, nifefuridine, or one of the test compounds (10 μM) via a gravity-driven perfusion system. (5mM). Single-cell Ca 2+ imaging. Laser excitation was provided by 100 fs pulses at 780 nm (80 MHz) from a Ti:sapphire laser (Mai Tai Broadband, Spectra-Physics). The laser beam is scanned by a resonant galvanometer (General Scanning Lumonics) enabling fast (7.9kHz) bi-directional scanning on the x-axis and by a conventional linear galvanometer on the y-axis to provide 30 Full frame scan rate of frames / s. The laser beam was focused on the cells through an Olympus 40× water immersion objective (numerical aperture 0.8). The emitted fluorescenc...

Embodiment 3

[0165] Example 3: Optimization of RyR2-stabilized compounds from shoots to leads (Hit-to-lead)

[0166] 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 Figure 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.

[0167]

[0168] 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 compositions and methods comprising compounds capable of normalizing imbalances in neuronal calcium homeostasis. Also disclosed are methods involving the use of these compounds for the treatment of neuronal or neurological disorders including: Alzheimer's disease, Parkinson's disease, Huntington's disease, frontotemporal dementia, Pick's disease, chronic traumatic encephalopathy, traumatic brain injury, stroke, cerebellar ataxia, multiple sclerosis, Down's syndrome, and age-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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Patent Type & Authority Patents(China)
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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