Inhibitor of peroxisome proliferator-activated receptor alpha coactivator 1

A compound, a technology of pharmaceutical compounds, applied in the field of drugs for the treatment of diabetes, insulin resistance and metabolic syndrome, can solve problems such as cold contact insensitivity

Inactive Publication Date: 2008-04-23
坎皮纳斯州立大学 UNICAMP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, animals whose UCP-2 expression is genetically ablated do not become obese, however, unlike UCP-1 knockout animals, they are not sensitive to cold exposure

Method used

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  • Inhibitor of peroxisome proliferator-activated receptor alpha coactivator 1
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  • Inhibitor of peroxisome proliferator-activated receptor alpha coactivator 1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1: Effect of treating obese and diabetic mice with antisense oligonucleotide PGC-1α

[0046] · Identification of the animal model used:

[0047] First, the animal models used in these experiments were identified. Two different strains of mice, but with some genetic identity, were used, SW / Uni and CBA / Uni mice. These two strains are related and to the previously described AKR mice that are prone to diabetes and obesity when fed a high-fat diet (Rossmeisl M, Rim JS, Koza RA, Kozak LP 2003 Variation in type 2 diabetes-related traits in mouse strains susceptible to diet-induced obesity (changes in type 2 diabetes-associated features in a mouse strain prone to diet-induced obesity), Diabetes 52:1958-66). SW / Uni and CBA / Uni mice did not develop obesity or diabetes when treated with a standard rodent diet (Figure 1). However, when fed a high-fat diet, CBA / Uni mice became obese, while SW / Uni mice became obese and diabetic with baseline serum glucose levels above 16....

Embodiment 2

[0049] Embodiment 2: Effect of treating SW / Uni mice with antisense oligonucleotide PGC-1α

[0050] Mice of the SW / Uni strain, which develop both obese and diabetic phenotypes when fed a high-fat diet, were selected as the animal model for testing. In the first part to identify the effect of the antisense oligonucleotide PGC-1α (PGC-1α / AS), the ability of the compound to inhibit the expression of the target protein in the liver and adipose tissue of experimental animals was evaluated by immunoblotting technique. Figure 3a shows that PGC-1α / AS had a dose-dependent effect on the expression of target proteins in liver and adipose tissue when administered parenterally for 4 days in SW / Uni mice fed a high-fat diet. This effect was specific and did not interfere with the expression of structural proteins (actin and vimentin) in the same tissue (Fig. 3b).

[0051] Subsequently, when PGC-1α / AS was administered once daily at a dose of 1.0 nmol, PGC-1α expression suppressed metabolic ...

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Abstract

The present invention refers to the use of an antisense DNA oligonucleotide for the messenger RNA of the PGC-la protein, useful as drug for the treatment of diabetes mellitus, insulin resistance and metabolic syndrome. More specifically, the present invention deals with a compound used as drug, through enteral or parenteral route, preferably, with the property of inhibiting the protein expression peroxisome proliferator-activated receptor alpha Coactivator 1 (PGC-la) leading to the reduction of the blood glucose levels. It deals, therefore, with a pharmacological compound that promotes, in diabetic and insulin-resistant individuals, improvement of the glucose serum levels, increase of the plasmatic insulin concentration and reduction of insulin resistance. The present invention presents a more effective control of the glucose levels and acts beneficially on other complications associated to the Diabetes and obesity conditions, according to tests performed in animal models. In this manner, the principal advantage of the present invention over others alike already existing in the market is the effectiveness that controls blood glucose levels and the fact of acting beneficially on other complications that accompany the disease.

Description

field of invention [0001] The present invention relates to the use of oligonucleotides as medicaments for the treatment of diabetes, insulin resistance and metabolic syndrome. [0002] More specifically, the present invention relates to compounds useful as medicaments, which can be administered enterally or parenterally, and which inhibit peroxisome proliferator-activated receptor alpha coactivator 1 (PGC-1α ), and lead to lowering of blood glucose levels. Accordingly, the present invention relates to pharmaceutical compounds that promote improved serum levels of glucose, increased plasma insulin concentrations and decreased resistance to insulin in diabetic and insulin-resistant individuals. The present invention has great social benefits, and from a commercial point of view, the present invention will also bring great benefits to the pharmaceutical industry. Background of the invention [0003] During the past decade, an increasing incidence of obesity and type 2 diabete...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H21/00A61K31/7088A61K31/7105A61K48/00A61P3/08C12N15/113C12N15/63
CPCC07H21/00C12N15/113C12N2310/11A61P3/00A61P3/08A61P3/10A61P5/50A61P43/00C12N15/00
Inventor L·A·维罗索C·T·德苏扎
Owner 坎皮纳斯州立大学 UNICAMP
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