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S1PR4-targeting composition for preventing or treating non-alcoholic steatohepatitis

A steatohepatitis, non-alcoholic technology, applied in the direction of active ingredients of phosphorus compounds, drug combinations, active ingredients of heterocyclic compounds, etc.

Active Publication Date: 2019-11-19
UNIV OF ULSAN FOUND FOR IND COOPERATION +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] On the other hand, FTY720 acts non-selectively on subtypes of sphingosine 1-phosphate receptors (S1P1, S1P2, S1P3, S1P4 and S1P5), resulting in Severe side effects centered on the cardiac circulatory system, such as decreased lymphocytes in the blood (lymphopenia) or bradycardia and arrhythmia, which can cause problems

Method used

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  • S1PR4-targeting composition for preventing or treating non-alcoholic steatohepatitis
  • S1PR4-targeting composition for preventing or treating non-alcoholic steatohepatitis
  • S1PR4-targeting composition for preventing or treating non-alcoholic steatohepatitis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Example 1. Selection of sphingolipid candidate substances

[0120] In order to derive lead candidates for the development of therapeutic agents for non-alcoholic steatohepatitis, from more than 600 kinds of sphingolipid compounds possessed by the sphingolipid library, we provided the combination of myriocin and FTY720 (fingolimod) 15 sphingolipid compounds with similar structures.

[0121] The results of measuring the agonistic activity related to sphingosine1-phosphate receptors using the GPCR activity measurement method of Discovex Corporation confirms that 2-amino-2-indicated by the following chemical formula 2 (2-(1-decyl-1H-1,2,3-triazol-4-yl)ethyl)propane-1,3-diol (hereinafter, referred to as SLB736) is susceptible to sphingosine 1-phosphate Body 4 has a specific agonistic effect.

[0122] Chemical formula 2:

Embodiment 2

[0123] Example 2. NLRP3 Inflammatory Body Inhibition Ability

[0124] It is well known that if the macrophages (Raw cells) are treated with lipopolysaccharide (LPS), the inflammasome (inflammasome) will be activated, and the production of interleukin-1β (IL-1β) will increase (Mariathasanet al ., Nat Rev Immunol. 2007; 17186029). In order to confirm the inhibitory effect of the inflammasome (NLRP3 inflammasome) activity, which is a representative inflammation-mediated protein, when lipopolysaccharide is processed on macrophages, the production amount of interleukin-1β as a candidate substance is measured and evaluated.

[0125] First, the raw cells (cell line) of the mouse macrophage cell line were treated with lipopolysaccharide (100ng / ml, Sigma-aldrich). After 12 hours, the in the culture medium could be observed. The concentration of interleukin-1β increased significantly.

[0126] As a control group, when macrophages were treated with myriocin at the same concentration and treat...

Embodiment 3

[0128] Example 3. Confirmation of the tissue and intracellular expression inhibitory effects related to the sphingosine 1-phosphate receptor 4 of SLB736

[0129] In order to confirm whether the compound SLB736 of the present invention acts as a functional inhibitor related to sphingosine 1-phosphate receptor 4, after administration of the candidate substance to non-alcoholic steatohepatitis model mice and mouse macrophages, The changes in sphingosine 1-phosphate receptor 4 protein expression were confirmed.

[0130] It is well known that if a methionine choline-deficinet diet (MCDD) is administered to mice, non-alcoholic steatohepatitis will occur. The experimental mice (C57BL / 6N, Orient Bio, Inc., Korea) were divided into three groups, and each group was fed only with methionine choline deficiency diet, methionine choline deficiency diet, and FTY720, 1mg / kg methionine choline deficiency diet After six weeks with 1 mg / kg of SLB736, the expression changes of sphingosine 1-phosphate...

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Abstract

The present invention relates to a S1PR4-targeting composition for preventing or treating non-alcoholic steatohepatitis and, more particularly, to a pharmaceutical composition and a health functionalfood composition, both comprising a sphingolipid compound which serves as a functional inhibitor against S1PR4, showing prophylaxis and therapy of non-alcoholic steatohepatitis. The sphingolipid compound of the present invention is expected to be applied as a leading material effective for the prevention or treatment of non-alcoholic steatohepatitis (NASH) as it has the effect of reducing the infiltration of inflammatory cells into hepatic tissues and suppressing fibrosis and decreases a level of liver injury (ALT), inflammation in hepatic tissues, and the expression of a fibrosis-related gene.

Description

Technical field [0001] The present invention relates to a composition for preventing or treating non-alcoholic steatohepatitis targeting sphingosine 1-phosphate receptor 4 (S1PR4). More specifically, the present invention relates to a pharmaceutical composition containing a sphingolipid compound And a health functional food composition, wherein the sphingolipid compound acts as a functional inhibitor related to the sphingosine 1-phosphate receptor 4 to prevent or treat non-alcoholic steatohepatitis. Background technique [0002] Myriocin isolated from Cordyceps fungus has long been known for its various pharmacological effects, and has been found to have the expected effect of non-alcoholic fatty acid liver disease (NAFLD) (Yang et al., Am J Physiol Endocrinol Metab. 2009; 19435851, Kurek et al., Liver Int. 2014; 24106929, Kasumov et al., PLos One. 2015; 25993337). However, due to the low safety margin of the substance, and animal experiments showed that it died due to severe di...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/42A61K31/66A23L33/10A61K31/4192
CPCA23L33/10A61K31/4192A61K31/42A61K31/66A61P1/16A61K45/06Y02A50/30A23V2002/00A23V2200/30A61K31/661
Inventor 高银熙李起业金相熙金大德
Owner UNIV OF ULSAN FOUND FOR IND COOPERATION