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Method of decreasing ubiquitylated protein levels

A technology of hydrates and halogen atoms, applied in organic chemistry, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve problems such as inefficiency

Inactive Publication Date: 2012-07-11
RGT UNIV OF CALIFORNIA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

UPS Becomes Less Efficient With Age

Method used

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  • Method of decreasing ubiquitylated protein levels
  • Method of decreasing ubiquitylated protein levels
  • Method of decreasing ubiquitylated protein levels

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0525] In vitro effect of ST101 on β-amyloid in neuronal 2a cultured cells

[0526] Neuro 2a is a murine neuroblastoma cell line known to produce the amyloid peptide Aβ in detectable amounts by ELISA assay 1-40 and Aβ 1-42 . These forms of Aβ have been associated with pathology in the AD brain, and it is specifically assumed that Aβ 1-42 Has the ability to block alpha 7 nicotine receptors and produce direct neurotoxic effects. Neuro2a cells were treated with ST101 added to tissue culture medium for 24 hours. Tissue culture media was harvested and analyzed by ELISA for the presence of Aβ.

[0527] attached figure 1 A and 1B are bar graphs depicting the effect of compound ST101 on Aβ production by Neuro 2a cells. figure 1 A is a bar graph depicting Aβ concentration in cell culture media as a function of ST101 concentration compared to control. figure 1 B depicts Aβ as a function of ST101 concentration compared to control 1-42 with Aβ 1-40 A bar graph of the ratio. as i...

Embodiment 2

[0529] Effect of ST101 on 3×Tg-AD mice in Morris water maze

[0530] The laboratory of Dr. Frank LaFerla at UC Irvine has developed transgenic mice containing 3 mutations associated with Alzheimer's pathology (βAPPSwe, PS1M146V, and τP301L) (Oddo et al., "Triple-transgenic model of AD with plaques and tangles: intracellular Aβ and synaptic dysfunction (A three-part transgenic model of AD with plaques and tangles: intracellular Aβ and synaptic dysfunction), Neuron 39(3):409-21 (2003)). These mutations switch APP cleavage from α-secretase to β-secretase, increasing Aβ 1-42 The generation of τ accumulates into double helical filaments. 3×Tg-AD animals developed the requisite features of AD in an age-dependent fashion with deficits in memory-related behavioral functions, plaque and tangle pathology, and synaptic dysfunction, which included deficits in long-term potentiation, which Activity considered to be critical for memory (Oddo et al., 2003). Furthermore, plaque formation p...

Embodiment 3

[0539] Effect of ST101 on Aβ in brain tissues derived from 3×Tg mice-AD

[0540] Biochemical implications: ST101 and the amyloid processing pathway

[0541] At the end of the 2-month treatment period, 3xTg mice were sacrificed and brain tissue processed. In the first assay, soluble Aβ was quantified by ELISA 1-40 and Aβ 1-42 and insoluble Aβ (after formic acid extraction). Soluble Aβ indicates protein that has been processed and released from full-length APP. Insoluble Aβ represents the fibrillar accumulations that eventually settle in amyloid plaques.

[0542] image 3 A and 3B are bar graphs depicting the effect of ST101 on Aβ in brain tissue derived from 3xTg mice-AD. image 3 A depicts soluble Aβ in the brain tissue of ST101-treated mice relative to control mice 1-40 and Aβ 1-42 amount. image 3 B depicts insoluble Aβ in mice treated with ST101 relative to control mice 1-40 and Aβ 1-42 A bar graph of the amount of (formic acid extraction). One animal in the ST1...

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Abstract

The present invention provides a method of decreasing the level of ubiquitylated protein in a subject, the method comprising administering a heterocyclic compound disclosed herein or a pharmaceutically acceptable salt, hydrate or prodrug thereof to a subject in need thereof.

Description

field of invention [0001] The present invention relates to the processing of proteins targeted for degradation by ubiquitination. Background of the invention [0002] Alzheimer's disease (AD) is a neurodegenerative disorder for which only symptomatic treatments of limited efficacy exist. Certain amyloid-β (Aβ) fragments of APP, especially Aβ, have been implicated in AD pathology 1-40 and Aβ 1-42 . A[beta] reduction has been pursued as a way to improve the AD process (Barten, D. and C. Albright, Mol. Neurobiol. 37:171-186 (1998)). However, to date, this approach has not resulted in an approved therapy. [0003] Attempts have been made to treat AD using active and passive immunization against Aβ. One such immunization approach has failed in human testing (Holmes, C. et al., Lancet 372:216-23 (2008)). A limitation of Aβ immunotherapy may be that it only targets already formed Aβ. It did not slow down or interrupt the production of new Aβ, and in fact, may even promote th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4166
CPCA61K31/429A61K31/4188A61K31/4745A61K31/437A61P19/08A61P21/00A61P21/02A61P25/00A61P25/16A61P25/28A61P27/00A61P27/02A61P27/12A61P29/00A61P35/00A61P37/08A61P43/00A61P9/00A61P3/10A61K31/4166A61K31/4184C07D235/02
Inventor 金·尼古拉斯·格林埃卡德·韦伯蒂尔曼·奥尔特尔斯朵夫沙伦·罗格斯弗兰克·拉夫尔拉
Owner RGT UNIV OF CALIFORNIA
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