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Treatment of type II diabetes and diabets-associated diseases with safe chemical mitochondrial uncouplers

A technology for mitochondrial uncoupling and metabolic diseases, applied in the fields of urinary system diseases, metabolic diseases, sensory diseases, etc.

Inactive Publication Date: 2013-11-27
新泽西医科和牙科大学
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

But these treatments eventually develop resistance or tolerance in patients

Method used

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  • Treatment of type II diabetes and diabets-associated diseases with safe chemical mitochondrial uncouplers
  • Treatment of type II diabetes and diabets-associated diseases with safe chemical mitochondrial uncouplers
  • Treatment of type II diabetes and diabets-associated diseases with safe chemical mitochondrial uncouplers

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preparation example Construction

[0164] The preparation of prodrugs is well known in the art and is described, for example, in Medicinal Chemistry: Principles and Practice, edited by F.D. King, Royal Society of Chemistry (Cambridge, UK) , 1994 noon; Hydrolysis in Drug and Prodrug Metabolism (Hydrolysis in Drug and Prodrug Metabolism), Chemistry, Biochemistry and Enzymology, author: B.Testa, J.M.Mayer, VCHA and Wiley-VCH Press, Zurich, Switzerland, 2003; Practical Medicinal Chemistry (The Practice of Medicinal Chemistry), C. Edited by G Wermuth, Academic Press, San Diego, CA, 1999.

[0165] The compounds of the present invention can be prepared by exemplary methods used by those skilled in the art as described in the relevant publications.

Embodiment 1

[0185] Acute treatment with 5-chloro-salicyl-(2-chloro-4-nitro)aniline 2-aminoethanol salt (CSAA) effectively reduces blood glucose in diabetic and pre-diabetic mice. The structure of CSAA is shown in Figure 1A middle. To assess the effect of CSAA on glycemic control, we injected saline solution containing CSAA into diabetic db / db mice or pre-diabetic C57 / B16 mice fed a high-fat diet for 10 weeks. As shown in Figure 1, with CSAA treatment, blood glucose concentrations started to decrease about 1 hour after treatment and remained effective for about 4 hours. Significant decreases in blood glucose concentrations were observed in both mouse strains. This was particularly pronounced in db / db mice, which showed a 30% reduction in blood sugar relative to controls. These results indicate that CSAA has an acute effect of lowering blood glucose concentrations in diabetic and pre-diabetic mouse models.

Embodiment 2

[0187] The acute effect of CSAA on lowering blood glucose concentrations is associated with activation of AMP-activated kinase (AMPK) and increased glucose uptake in tissues. Mitochondrial uncoupling reduces the efficiency of ATP production, which in turn induces a compensatory upregulation of glucose uptake. To test this theory, we measured the level of phosphorylated AMPK, which reflects AMPK activity in the liver of mice injected with CSAA. In response to an increase in AMP (adenosine monophosphate), ATP decreases and as a result AMPK is activated. Such as figure 2 As shown in A, indeed, acute treatment with CSAA significantly increased the levels of phosphorylated AMPK. Furthermore, we directly measured the rate of glucose uptake in different tissues of mice acutely treated with CSAA. Such as figure 2 As shown in B, glucose uptake rates were significantly elevated in liver, muscle, kidney, and lung, but not in brain or white adipose tissue (WAT). At the same time, the...

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Abstract

This application discloses methods for treating, preventing and / or alleviating the symptoms of type II diabetes and diabetes-related disorders or complications. The invention provides a novel approach to treating and managing disorders and symptoms related to elevated plasma glucose concentrations and insulin resistance, characterized by few side effects and low toxicity. In particular, the invention provides 2-hydroxy-benzoic anilide compounds and derivatives, and compositions thereof, which can control blood-glucose and increase insulin sensitivity by reducing plasma glucose concentration and cellular energy efficiency.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application 61 / 414,030, filed November 16, 2010, which is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to compounds, compositions and novel methods for treating and / or preventing type II diabetes and its related diseases and complications by uncoupling mitochondria. [0004] Statement Regarding Federally Funded Research [0005] This invention was funded in whole or in part by grants from the National Institutes of Health (grant numbers: 1R01CA116088 and 1R01AG030081). The US Government has certain rights in this invention. Background technique [0006] Type 2 diabetes mellitus is a metabolic disease of adults characterized by elevated blood glucose concentrations and insulin resistance in surrounding tissues. In the United States alone, approximately 20 million people suffer from ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/165
CPCA61K31/165A61K31/609A61K31/155A61K45/06A61P1/00A61P1/16A61P13/12A61P25/02A61P25/16A61P25/28A61P27/02A61P3/00A61P3/04A61P35/00A61P3/06A61P3/08A61P9/00A61P9/04A61P9/10A61P9/12A61P3/10A61K2300/00
Inventor S·金
Owner 新泽西医科和牙科大学
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