TAK-875 medicine composition based on GPR40 agonist
By reducing the expression of GPR40, it has solved the problem of withdrawal due to hepatotoxicity in clinical trials, realized its potential as an anti-hepatocellular drug, and protected its medical use as an anti-cancer drug.
Patent Information
- Application Number
- CN202411848953.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-16
- Publication Date
- 2025-03-07
AI Technical Summary
The TAK-875 drug was withdrawn due to hepatotoxicity problems in the Phase III clinical trial, and its hepatotoxicity mechanism is unknown, which affects its medical use as an anti-hepatocellular carcinoma drug.
Through research, it was found that ferrodysfunction inhibitors can save liver ferrodystrophy. The hepatotoxicity of TAK-875 is dependent on the GPR40 target. The higher the GPR40 expression in hepatocytes, the stronger the hepatotoxicity of TAK-875. Therefore, the composition of TAK-875 drugs based on GPR40 agonist reduces hepatotoxicity by reducing GPR40 expression.
By reducing GPR40 expression, the hepatotoxicity of TAK-875 can be reduced, giving it potential as an anti-hepatic cancer candidate and protecting its medicinal use as an anti-cancer drug.
Smart Images
Figure CN119564660A_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of TAK-875 drugs, and in particular to a TAK-875 drug composition based on a GPR40 agonist. Background Art
[0002] GPR40 is a G protein-coupled receptor that can be activated by medium- and long-chain fatty acids. It plays a significant role in promoting insulin release, regulating glucose homeostasis, and preventing and treating type 2 diabetes. TAK-875 is a GPR40 / FFAR1 allosteric agonist that increases insulin secretion in a glucose-dependent manner and promotes the secretion of GLP1 by intestinal L cells. However, it withdrew from the Phase III clinical trial due to a 3-7-fold increase in ALT / AST and hepatotoxicity. The mechanism of TAK-875 hepatotoxicity is unclear. Our study found that ferroptosis inhibitors can rescue liver ferroptosis, and the hepatotoxicity of TAK-875 is GPR40 target-dependent. The higher the GPR40 expression in hepatocytes, the stronger the hepatotoxicity of TAK-875. At the protein level, the GPR40 expression in liver cancer cells is much higher than that in normal liver cells. Summary of the invention
[0003] The technical problem to be solved by the present invention is to overcome the above technical defects.
[0004] In order to solve the above problems, the technical solution of the present invention is: TAK-875 drug composition based on GPR40 agonist, its chemical formula is: 29 H 32 O7S·1 / 2H2O, comprising a benzofuran ring, wherein the benzofuran ring is connected with a carboxyl group and a methoxy group, the methoxy group is connected to a biphenyl structure through a longer carbon chain, the biphenyl structure is composed of two benzene rings, the two benzene rings are connected through a carbon-carbon bond, one of the benzene rings is connected with a methylsulfonyl group and an ether bond, and the other benzene ring is connected with a methyl group and a carbon chain connected to the benzofuran ring.
[0005] Furthermore, the TAK-875 contains chiral carbon atoms, ie, carbon atoms with different spatial configurations.
[0006] The advantages of the present invention compared with the prior art are:
[0007] In the present invention, the hepatotoxicity of TAK-875 is GPR40 target-dependent. The higher the GPR40 expression in hepatocytes, the stronger the hepatotoxicity of TAK-875. At the protein level, the GPR40 expression in hepatoma cells is much higher than that in normal hepatocytes. Therefore, TAK-875 can be used as a candidate drug for anti-liver cancer. We want to protect the medical use of TAK-875 as an anti-cancer drug. BRIEF DESCRIPTION OF THE DRAWINGS
[0008] Figure 1 This is a data graph showing that the sensitivity of the GPR40 knockdown group based on the GPR40 agonist TAK-875 drug composition of the present invention to TAK-875 is reduced.
[0009] Figure 2 It is a schematic diagram of the high expression of GPR40 in liver cancer cell HepG2 compared with normal liver cell THLE2 composed of TAK-875 drug based on GPR40 agonist of the present invention. DETAILED DESCRIPTION
[0010] The specific implementation of the present invention is further described below in conjunction with the accompanying drawings, wherein the same components are represented by the same reference numerals.
[0011] It should be noted that the words "front", "rear", "left", "right", "up" and "down" used in the following description refer to directions in the drawings, and the words "inside" and "outside" refer to directions toward or away from the geometric center of a specific component, respectively.
[0012] In order to make the contents of the present invention more clearly understood, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings in the embodiments of the present invention.
[0013] like Figure 1 to Figure 2 As shown, the TAK-875 drug composition based on the GPR40 agonist has a chemical formula of: C29H32O7S·1 / 2H2O, including a benzofuran ring, a carboxyl group and a methoxy group are connected to the benzofuran ring, the methoxy group is connected to the biphenyl structure through a longer carbon chain, the biphenyl structure is composed of two benzene rings, and the two benzene rings are connected by a carbon-carbon bond, one of the benzene rings is connected to a methylsulfonyl group and an ether bond, and the other benzene ring is connected to a methyl group and a carbon chain connected to the benzofuran ring, and the TAK-875 contains chiral carbon atoms, that is, carbon atoms with different spatial configurations.
[0014] The present invention and its embodiments are described above, and such description is not restrictive. The drawings show only one embodiment of the present invention, and the actual structure is not limited thereto. In short, if ordinary technicians in the field are inspired by it, without departing from the purpose of the invention, they can design a structure and embodiment similar to the technical solution without creativity, which should belong to the protection scope of the present invention.
Claims
1. TAK-875 drug composition based on GPR40 agonist, characterized in that: Its chemical formula is: C 29 H 32 O7S·1 / 2H2O, comprising a benzofuran ring, wherein the benzofuran ring is connected with a carboxyl group and a methoxy group, the methoxy group is connected to a biphenyl structure through a longer carbon chain, the biphenyl structure is composed of two benzene rings, the two benzene rings are connected through a carbon-carbon bond, one of the benzene rings is connected with a methylsulfonyl group and an ether bond, and the other benzene ring is connected with a methyl group and a carbon chain connected to the benzofuran ring.
2. The TAK-875 drug composition based on the GPR40 agonist according to claim 1, characterized in that: The TAK-875 contains chiral carbon atoms, ie, carbon atoms with different spatial configurations.