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Composition and method for treating proteinuria

A technology of high protein and composition, which is applied in the direction of drug combination, pharmaceutical formula, active ingredients of heterocyclic compounds, etc., and can solve problems such as reducing urinary protein

Inactive Publication Date: 2010-12-15
史跃年
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it must be pointed out that although pirfenidone slows the loss of renal function in the above open experiments, there is no data showing that pirfenidone can reduce urinary protein (Cho M.E., et al: Pirfenidone slows renal function declinein patients with focal segmental glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 2: 906-913, 2007)

Method used

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  • Composition and method for treating proteinuria
  • Composition and method for treating proteinuria
  • Composition and method for treating proteinuria

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0054] Example 1 Inhibition of activation of p38 by AKF-PD

[0055] There are three types of proteins in the MAPK family: Erk1 / 2, p38, and JNK. p38 kinase is activated by phosphorylation of the retained Thr-Gly-Tyr in its activation compartment. Activated p38 can further phosphorylate many targets in the cell and nucleus, leading to cellular responses such as apoptosis, inflammation and fibrosis. We first analyzed the anti-inflammatory effect of AKF-PD using the p38 delivery system in endotoxin-stimulated mouse macrophages (RAW264.7). Mouse macrophages (RAW264.7) were pretreated with AKF-PD or pirfenidone (PFD) for 4 hours, and then stimulated with endotoxin for 30 minutes. Such as figure 1 As shown, the p38 activity of endotoxin-treated cells was significantly increased. AKF-PD ( figure 1 A) and PFD ( figure 1 B) All of them significantly inhibited the activity of p38 stimulated by LPS. AKF-PD and PFD should have no effect on the stability of p38 protein, judging from ...

Embodiment 2

[0057] Inhibitory effects of AKF-PD and PFD on the synthesis of TNF-α mRNA in mouse macrophages

[0058] Macrophages are an important source of TNF-α and other pro-inflammatory cytokines for rheumatoid arthritis, and many pathways including p38MAPK may be involved in endotoxin-induced TNF-α production in these cells. Therefore we studied the effect of AKF-PD on the gene expression of TNF-α. The level of TNF-α mRNA in endotoxin-stimulated cells increased 6-fold. Both AKF-PD and PFD inhibited the synthesis of TNF-α mRNA in a dose-dependent manner ( figure 2 ). At about 500 μg / ml, the inhibition rate can reach 50%.

Embodiment 3

[0060] Inhibitory effect of AKF-PD on the synthesis and secretion of TNF-α protein in macrophages

[0061] The effects of AKF-PD on the synthesis and secretion of TNF-α protein were analyzed with endotoxin-activated mouse macrophages (RAW264.7). Cells were pretreated with AKF-PD and then activated with endotoxin. The secreted and intracellular TNF-α protein was measured simultaneously. Consistent with the effect of suppressing mRNA, cells pretreated with AKF-PD also inhibited the protein level of TNF-α in a dose-dependent manner ( image 3 ). AKF-PD at a concentration of 100 μg / ml can reduce the secretion of TNF-α by 64%. When the concentration increased to 300 μg / ml, AKF-PD could reduce the secretion of TNF-α by 89% ( image 3 A). AKF-PD can also reduce the amount of TNF-α in cells, but the inhibitory effect is very low, reaching about 50% inhibition at the concentration of 300 μg / ml ( image 3 B). Therefore, the above results indicate that AKF-PD can significantly and d...

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Abstract

The present invention discloses 5-methyl-l-(substituted phenyl)-2(lH)-pyridones having the ability to reduce proteinuria and for treating kidney diseases. The ability to reduce proteinuria has a renoprotective effect for slowing the progression of kidney diseases. A representative example of 5-methyl-(l-substituted phenyl)-2(lH)-pyridones is l-(3'-fluorophenyl)-5-methyl-2(lH)-pyridone, AKF-PD. Accordingly, the invention provides compositions comprising one or more compounds selected from the group consisting of 5-methyl-l-(substituted phenyl)-2(lH)-pyridones and methods of using the same to treat proteinuria and kidney diseases.

Description

[0001] In the present invention, multiple references or patent publications are cited, so these documents or publications are incorporated into the present invention as a reference in order to have a more complete description of the technical content of the present invention. technical field [0002] The present invention relates to a pharmaceutical composition containing 5-methyl-1-(substituted phenyl)-2-(1H)pyridinone compound and a method for treating hyperproteinuria by using the composition. Because high proteinuria is one of the main symptoms of chronic kidney disease, the treatment of high proteinuria should improve the renal function of chronic kidney disease and slow down the deterioration of the disease. Background technique [0003] Each year, more than 100,000 new patients with kidney failure, the final stage of chronic kidney disease (CKD), are diagnosed in the United States. Diabetes and hypertension are the two most common causes of kidney disease (United Stat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/90A61K31/4418A61P13/02A61P13/12
CPCA61K31/44A61P13/02A61P13/12
Inventor 史跃年
Owner 史跃年
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