Application of FOXM1 inhibitor FDI-6 in resistance of hepatic fibrosis

Abstract

The invention discloses application of an FOXM1 inhibitor FDI-6 in resistance of hepatic fibrosis. The name of a derivative is 3-amino-N-(4-fluorophenyl)-6-(thiophene-2-ox)-4-(trifluoromethyl)thieno[2,3-b]pyridine-2-formamide; an action mechanism is expressed by inhibiting FOXM1; the expression of Collagen I and alpha-SMA is regulated down, so as to realize the corresponding hepatic fibrosis-resistant function. The caused hepatic fibrosis diseases include but not limited to chronic viral hepatitis, alcoholic hepatic diseases, non-alcoholic fatty hepatic diseases, toxin, drug-derived and autoimmunity hepatic diseases, hepatic blood stasis, inherited metabolic diseases and the like.

Description

technical field

[0001] The present invention relates to a FOXM1 inhibitor FDI-6 and the application of the compound in anti-hepatic fibrosis. Background technique

[0002] Liver fibrosis is closely related to the chronic inflammatory response of the liver, which develops from mild inflammatory response to severe inflammatory response, and finally to liver fibrosis and even cirrhosis. This process includes chronic viral hepatitis, alcoholic liver disease, non-inflammatory Most chronic liver diseases, including alcoholic fatty liver disease, toxins and drugs, autoimmune liver disease, liver congestion and genetic metabolic diseases, etc., follow the common pathological process. Hepatic fibrosis is currently considered to be a reversible pathological process in which the proliferation and degradation of extracellular matrix (ECM) such as collagen in the liver is unbalanced, leading to abnormal deposition of fibrous connective tissue in the liver, reflecting a balanced process o...

Examples

Embodiment 1

[0035] Example 1: Analyzing clinical samples through the more severe liver fibrosis—cirrhosis tissue gene expression profile (gene expression omnibus, GEO) database on the Internet.

[0036] Experimental materials: two liver cirrhosis databases, GSE25097 and GSE 14323.

[0037] Experimental method: The GEO database GSE25097 and GSE 14323 of liver cirrhosis were investigated online to screen the differential expression of FOXM1.

[0038] Experimental results: Both databases showed that the expression of FOXM1 in cirrhotic tissues was significantly higher than that in normal tissues.

Embodiment 2

[0039] Example 2: Left middle common bile duct ligation (LMBDL) induced liver fibrosis in mice.

[0040] Experimental materials: C57L / 6 mice, 3% sodium pentobarbital solution, surgical instruments.

[0041] Experimental method: 12-week-old male C57BL / 6 mice were anesthetized by intraperitoneal injection of 3% pentobarbital sodium solution, the skin and muscle layer of the abdominal cavity were incised, the common bile duct was freed, the left middle common bile duct was ligated, and the abdominal cavity was sutured.

[0042] Experimental results: After about 10 days, ALT and AST were significantly increased, and HE and Sirius red staining showed obvious liver fibrosis.

Embodiment 3

[0043] Embodiment 3: carbon tetrachloride (CCl 4 ) induced liver fibrosis in mice.

[0044] Experimental materials: C57L / 6 mice, CCl 4 solution, olive oil, 1ml syringe.

[0045] Experimental method: 12-week-old male C57BL / 6 mice were intraperitoneally injected with CCl diluted in olive oil 4 Solution (by volume ratio, CCl 4 : olive oil = 1: 3) twice a week.

[0046] Experimental results: After about 4 weeks, both ALT and AST were significantly increased, and HE and Sirius red staining showed obvious liver fibrosis.

technical field

[0001] The present invention relates to a FOXM1 inhibitor FDI-6 and the application of the compound in anti-hepatic fibrosis. Background technique

[0002] Liver fibrosis is closely related to the chronic inflammatory response of the liver, which develops from mild inflammatory response to severe inflammatory response, and finally to liver fibrosis and even cirrhosis. This process includes chronic viral hepatitis, alcoholic liver disease, non-inflammatory Most chronic liver diseases, including alcoholic fatty liver disease, toxins and drugs, autoimmune liver disease, liver congestion and genetic metabolic diseases, etc., follow the common pathological process. Hepatic fibrosis is currently considered to be a reversible pathological process in which the proliferation and degradation of extracellular matrix (ECM) such as collagen in the liver is unbalanced, leading to abnormal deposition of fibrous connective tissue in the liver, reflecting a balanced process o...

Examples

Embodiment 1

[0035] Example 1: Analyzing clinical samples through the more severe liver fibrosis—cirrhosis tissue gene expression profile (gene expression omnibus, GEO) database on the Internet.

[0036] Experimental materials: two liver cirrhosis databases, GSE25097 and GSE 14323.

[0037] Experimental method: The GEO database GSE25097 and GSE 14323 of liver cirrhosis were investigated online to screen the differential expression of FOXM1.

[0038] Experimental results: Both databases showed that the expression of FOXM1 in cirrhotic tissues was significantly higher than that in normal tissues.

Embodiment 2

[0039] Example 2: Left middle common bile duct ligation (LMBDL) induced liver fibrosis in mice.

[0040] Experimental materials: C57L / 6 mice, 3% sodium pentobarbital solution, surgical instruments.

[0041] Experimental method: 12-week-old male C57BL / 6 mice were anesthetized by intraperitoneal injection of 3% pentobarbital sodium solution, the skin and muscle layer of the abdominal cavity were incised, the common bile duct was freed, the left middle common bile duct was ligated, and the abdominal cavity was sutured.

[0042] Experimental results: After about 10 days, ALT and AST were significantly increased, and HE and Sirius red staining showed obvious liver fibrosis.

Embodiment 3

[0043] Embodiment 3: carbon tetrachloride (CCl 4 ) induced liver fibrosis in mice.

[0044] Experimental materials: C57L / 6 mice, CCl 4 solution, olive oil, 1ml syringe.

[0045] Experimental method: 12-week-old male C57BL / 6 mice were intraperitoneally injected with CCl diluted in olive oil 4 Solution (by volume ratio, CCl 4 : olive oil = 1: 3) twice a week.

[0046] Experimental results: After about 4 weeks, both ALT and AST were significantly increased, and HE and Sirius red staining showed obvious liver fibrosis.

Images