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WO-2026092667-A1 - USE OF COMPOUND OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF IN TREATMENT OF LIPID METABOLIC DISEASES

WO2026092667A1WO 2026092667 A1WO2026092667 A1WO 2026092667A1WO-2026092667-A1

Abstract

Provided is the use of a compound or a pharmaceutically acceptable salt thereof in the treatment of lipid metabolic diseases. The compound or pharmaceutically acceptable salt thereof can significantly reduce body weight and improve the metabolic phenotype of diseases associated with lipid metabolism. The compound or pharmaceutically acceptable salt thereof is capable of reducing the expression of triglycerides, total cholesterol, and alkaline phosphatase, improving blood lipid level of the body, and reducing lipid accumulation in adipose tissue.

Inventors

  • QIU, Yan
  • ZHANG, FENG
  • DU, ZHIQIANG
  • Chang, Xiaohui

Assignees

  • 通化东宝药业股份有限公司

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241101

Claims (10)

  1. The use of compounds of the following formula or pharmaceutically acceptable salts thereof in the preparation of medicaments having functions selected from: 1) Lower triglycerides; 2) To treat or prevent diseases related to triglycerides; 3) Lower total cholesterol; 4) To treat or prevent diseases related to total cholesterol; 5) Lowering high-density lipoprotein; 6) To treat or prevent diseases associated with high-density lipoprotein; 7) Lower LDL cholesterol; 8) To treat or prevent diseases associated with low-density lipoprotein; 9) Reduce alkaline phosphatase expression; and, 10) Reduce liver fat; The compound or a pharmaceutically acceptable salt thereof is as follows: SEQ ID NO:1：YAibEGT FTSDY SIAibLD KK 1 AZ 0 K 0 Z 1 FZ 2 E 0 W LZ 3 AGGPSSGAPPPS 0 ; SEQ ID NO:2: YAibEGT FTSDY SIAibLD KE 0 AQK 0 AFVK 1 W LIAGGPSSGA PPPS 0 ; SEQ ID NO:3：YAibEGT FTSDY SIE 0 LD KK 0 AQK 1 AFVQW LIAGGPSSGA PPPS 0 ; SEQ ID NO:4：YAibEGT FTSDY SIE 0 LD K 0 IAQK 1 AFVQW LIAGGPSSGA PPPS 0 ; in, The structure of Aib is S 0 is selected from Z0 is selected from glutamine (Q) and asparagine (N); Z1 is selected from alanine (A) and glutamic acid (E); Z2 is selected from valine (V) and isoleucine (I); Z3 is selected from isoleucine (I) and leucine (L); E0 and K0 indicate that the carboxyl group on the glutamic acid side chain and the amino group on the lysine side chain together form a lactam. In this case , the structure of K0Z1FZ2E0 is ... The structure of E 0 AQK 0 is The structure of E 0 LDKK 0 is The structure of E 0 LDK 0 is as follows K1 indicates that the amino group on the lysine side chain is linked to -XX1 - X2 , and its structure is: X is selected from R1 and R2 are independently selected from H and CH3 , respectively; X 1 is selected from X 2 is selected from m, n, and p are independently selected from 2 and 3, respectively; s is selected from 2 and 3; q is selected from 15, 16, 17, 18, and 19; Preferably, the compound is selected from: More preferably, the drug is administered once every 1-30 days, for example once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month; and/or, The dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg/kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng/kg, 1 ng/kg, 10 ng/kg, 20 ng/kg, 30 ng/kg, 40 ng/kg, 50 ng/kg, 60 ng/kg, 70 ng/kg, 80 ng/kg, 90 ng/kg, 100 ng/kg, 110 ng/kg, 120 ng/kg, 130 ng/kg, 140 ng/kg, 150 ng/kg, 160 ng/kg, 170 ng/kg, 180 ng/kg, 190 ng/kg or 200 ng/kg.
  2. The application as described in claim 1, characterized in that, 1) The triglyceride-related diseases mentioned are selected from at least one of the following: hyperlipidemia, atherosclerosis, coronary heart disease, and nephrotic syndrome; 2) The diseases associated with total cholesterol are selected from at least one of the following: atherosclerosis and nephrotic syndrome; 3) The diseases associated with high-density lipoprotein are selected from: primary biliary cholangitis; or, 4) The diseases associated with low-density lipoprotein are selected from at least one of the following: atherosclerosis and coronary heart disease.
  3. The application as described in claim 1 or 2 is characterized in that, 1) The triglyceride-related diseases or patients therein are suitable for a dosing frequency of once every 1 to 30 days, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month; 2) For the aforementioned diseases related to total cholesterol or for patients thereof, a dosing frequency of once every 1 to 30 days is appropriate, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month; or, 3) For patients with the aforementioned high-density lipoprotein-related diseases, a dosing frequency of once every 1 to 30 days is appropriate, such as once a day, once every two days, once every three days, once every seven days, once every two weeks, or once a month.
  4. The use of the compound as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a total cholesterol inhibitor, a high-density lipoprotein inhibitor or a low-density lipoprotein inhibitor; Preferably, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg/kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng/kg, 1 ng/kg, 10 ng/kg, 20 ng/kg, 30 ng/kg, 40 ng/kg, 50 ng/kg, 60 ng/kg, 70 ng/kg, 80 ng/kg, 90 ng/kg, 100 ng/kg, 110 ng/kg, 120 ng/kg, 130 ng/kg, 140 ng/kg, 150 ng/kg, 160 ng/kg, 170 ng/kg, 180 ng/kg, 190 ng/kg or 200 ng/kg.
  5. The use of the compound as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament having two or more of the following functions; 1) Suppresses appetite; 2) Improves insulin sensitivity; 3) Reduce glycated hemoglobin; 4) Inhibits alanine aminotransferase; 5) Inhibits aspartate aminotransferase; 6) Lowers triglycerides; 7) Lower total cholesterol; 8) Lowering high-density lipoprotein; 9) Lowering LDL cholesterol; and, 10) Reduce alkaline phosphatase expression; Preferably, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg/kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng/kg, 1 ng/kg, 10 ng/kg, 20 ng/kg, 30 ng/kg, 40 ng/kg, 50 ng/kg, 60 ng/kg, 70 ng/kg, 80 ng/kg, 90 ng/kg, 100 ng/kg, 110 ng/kg, 120 ng/kg, 130 ng/kg, 140 ng/kg, 150 ng/kg, 160 ng/kg, 170 ng/kg, 180 ng/kg, 190 ng/kg or 200 ng/kg.
  6. The use of the compound as defined in claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating two or more of the following diseases; 1) Diseases related to appetite; 2) Insulin-related diseases; 3) Diseases related to glycated hemoglobin; 4) Diseases related to alanine aminotransferase; 5) Diseases related to aspartate aminotransferase; 6) Diseases related to triglycerides; 7) Diseases related to total cholesterol; 8) Diseases related to high-density lipoprotein; 9) Diseases related to low-density lipoprotein; 10) Diseases related to alkaline phosphatase; 11) Fatty liver; and, 12) Diseases caused by leptin receptor deficiency; Preferably, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg/kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng/kg, 1 ng/kg, 10 ng/kg, 20 ng/kg, 30 ng/kg, 40 ng/kg, 50 ng/kg, 60 ng/kg, 70 ng/kg, 80 ng/kg, 90 ng/kg, 100 ng/kg, 110 ng/kg, 120 ng/kg, 130 ng/kg, 140 ng/kg, 150 ng/kg, 160 ng/kg, 170 ng/kg, 180 ng/kg, 190 ng/kg or 200 ng/kg.
  7. A method for treating or improving two or more of the following diseases, comprising administering to a subject in need an effective amount of a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof; said diseases being selected from: 1) Diseases related to appetite; 2) Insulin-related diseases; 3) Diseases related to glycated hemoglobin; 4) Diseases related to alanine aminotransferase; 5) Diseases related to aspartate aminotransferase; 6) Diseases related to triglycerides; 7) Diseases related to total cholesterol; 8) Diseases related to high-density lipoprotein; 9) Diseases related to low-density lipoprotein; 10) Diseases related to alkaline phosphatase; 11) Fatty liver; and, 12) Diseases caused by leptin receptor deficiency; Preferably, the dosage of the compound or a pharmaceutically acceptable salt thereof is within 0.2 mg/kg, and the dosage of the compound or a pharmaceutically acceptable salt thereof is, for example, 0.8 ng/kg, 1 ng/kg, 10 ng/kg, 20 ng/kg, 30 ng/kg, 40 ng/kg, 50 ng/kg, 60 ng/kg, 70 ng/kg, 80 ng/kg, 90 ng/kg, 100 ng/kg, 110 ng/kg, 120 ng/kg, 130 ng/kg, 140 ng/kg, 150 ng/kg, 160 ng/kg, 170 ng/kg, 180 ng/kg, 190 ng/kg or 200 ng/kg.
  8. The method as described in claim 7, wherein the method satisfies one or more of the following: 1) The diseases related to appetite mentioned are selected from: hyperthyroidism; 2) The insulin-related diseases are selected from at least one of the following: insulin resistance and insulin deficiency; 3) The diseases associated with glycated hemoglobin are selected from at least one of the following: hypertension, diabetic nephropathy, and hypothyroidism; 4) The diseases associated with alanine aminotransferase are selected from at least one of the following: viral hepatitis, alcoholic liver disease, fatty liver disease, and cirrhosis; 5) The diseases associated with aspartate aminotransferase are selected from at least one of the following: fatty liver disease and drug-induced liver injury; 6) The triglyceride-related diseases mentioned are selected from at least one of the following: hyperlipidemia, atherosclerosis, coronary heart disease, and nephrotic syndrome; 7) The diseases associated with total cholesterol are selected from at least one of the following: hepatitis, atherosclerosis, and nephrotic syndrome; 8) The diseases associated with high-density lipoprotein are selected from at least one of the following: chronic liver disease and primary biliary cholangitis; 9) The diseases associated with low-density lipoprotein are selected from at least one of the following: atherosclerosis and coronary heart disease; and, 10) The leptin receptor deficiency is leptin receptor knockout.
  9. The method as described in claim 7 or 8, characterized in that the method satisfies one or more of the following: 1) The application is performed via a route selected from topical and/or subcutaneous application; 2) The dosage is 1-30 nmol/kg, for example 1, 3, 5, 10, 15, 30 nmol/kg, preferably 15 nmol/kg; 3) The application can be a single application or repeated application, preferably repeated application; 4) The application is performed once a day, once every two days, once every three days, once every four days, once every five days, once every six days, once every seven days, once every eight days, once every nine days, or once every ten days; and, 5) The application lasts from one week to several months.
  10. The compound as defined in claim 1 or a pharmaceutically acceptable salt thereof is used to treat or improve two or more of the following conditions: 1) Diseases related to appetite; 2) Insulin-related diseases; 3) Diseases related to glycated hemoglobin; 4) Diseases related to alanine aminotransferase; 5) Diseases related to aspartate aminotransferase; 6) Diseases related to triglycerides; 7) Diseases related to total cholesterol; 8) Diseases related to high-density lipoprotein; 9) Diseases related to low-density lipoprotein; 10) Diseases related to alkaline phosphatase; 11) Fatty liver; and, 12) Diseases caused by leptin receptor deficiency.

Description

The use of a compound or a pharmaceutically acceptable salt thereof in the treatment of lipid metabolism disorders This application claims priority to Chinese patent application 2024115501779, filed on November 1, 2024. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field This invention relates to the field of biomedical technology, and in particular to the use of a compound or a pharmaceutically acceptable salt thereof in the treatment of lipid metabolism disorders. Background Technology In recent years, lipid metabolism has become a research hotspot, particularly its role in diseases such as cancer, diabetes, obesity, chronic kidney disease, neurodegenerative diseases, and liver disease. These studies not only focus on lipids themselves but also on the roles of fatty acids (FAs), especially polyunsaturated fatty acids (PUFAs). Lipid metabolism disorders, also known as lipid metabolism disturbances, refer to abnormalities in the metabolism of lipids (such as cholesterol and triglycerides) in the body, caused by genetic factors, environmental factors, or both. These diseases can increase the risk of cardiovascular disease and are among the most important diseases affecting human health today. In recent years, many innovative drugs have emerged in the research of lipid-lowering drugs. This research not only involves the fundamental theories of lipid metabolism but also includes new discoveries about drug targets, providing new insights into the treatment of atherosclerotic cardiovascular diseases. Cardiovascular disease is one of the most common and serious diseases among modern adults, and abnormal lipid metabolism is an independent risk factor for cardiovascular disease. Current research focuses not only on lipoprotein components and lipid metabolism, but also on the cardiovascular protective effects of glycine. Furthermore, research also investigates the roles and molecular mechanisms of the PCSK9/LDLR pathway, the small polypeptide EpK (mimicking the human apoE domain), polyunsaturated fatty acids, adiponectin, the LXR-ABCA1 pathway, and probucol in lipid metabolism. Common lipid metabolism disorders include hypercholesterolemia: elevated levels of total cholesterol (TC) or low-density lipoprotein cholesterol (LDL-C) in the blood; hypertriglyceridemia: elevated levels of triglycerides (TG) in the blood; mixed hyperlipidemia: the coexistence of high cholesterol and high triglycerides; low high-density lipoprotein cholesterol: decreased levels of high-density lipoprotein cholesterol (HDL-C) in the blood; and familial hypercholesterolemia: a hereditary disease characterized by abnormally elevated LDL-C levels. Many lipid-lowering drugs, especially statins, can cause side effects such as muscle pain and abnormal liver function. These side effects limit their use for some patients and may affect patient adherence. Different patients respond differently to the same drug. Some patients may respond well to a particular drug, while others may respond poorly or experience adverse reactions. The ideal target for lipid level control remains controversial. Different guidelines may propose different treatment goals, which introduces some confusion into clinical practice. Lipid-lowering drugs may interact with other medications, affecting their efficacy or increasing the risk of side effects. Although some drugs can effectively lower lipid levels in the short term, their long-term efficacy and safety require further clinical data to verify. In summary, existing drugs for treating lipid metabolism-related diseases have various problems, therefore, it is necessary to find a more suitable drug for treating lipid metabolism-related diseases. Summary of the Invention To address the issue of high-frequency injections required for medications treating lipid metabolism disorders in existing technologies, this invention provides the application of a compound or a pharmaceutically acceptable salt thereof in the treatment of lipid metabolism disorders. Compared to known weight-loss drugs in the art, the compound or pharmaceutically acceptable salt of this invention has a longer duration of action, which helps reduce the frequency of medication and improve patient adherence. In one aspect, this invention provides the use of compounds of the following formula or pharmaceutically acceptable salts thereof in the preparation of medicaments for lowering triglycerides; SEQ ID NO:1：YAibEGT FTSDY SIAibLD KK 1 AZ 0 K 0 Z 1 FZ 2 E 0 W LZ 3 AGG PSSGA PPPS 0 ; SEQ ID NO:2: YAibEGT FTSDY SIAibLD KE 0 AQK 0 AFVK 1 W LIAGG PSSGA PPPS 0 ; SEQ ID NO:3：YAibEGT FTSDY SIE 0 LD KK 0 AQK 1 AFVQW LIAGG PSSGA PPPS 0 ; SEQ ID NO:4: YAibEGT FTSDY SIE 0 LD K 0 IAQK 1 AFVQW LIAGG PSSGA PPPS 0 ; in, The structure of Aib is S 0 is selected from Z0 is selected from glutamine (Q) and asparagine (N); Z1 is selected from alanine (A) and glutamic acid (E); Z2 is selected from valine (V) and isole