WO2023096448A1 - Use of obatoclax in treating metabolic and fibrotic diseases - Google Patents

Abstract

The present invention relates to a use of Obatoclax in treating metabolic and fibrotic diseases, and more specifically, to a novel use of Obatoclax in preventing or treating metabolic and fibrotic diseases, wherein Obatoclax exhibits the effects of inhibiting lipid accumulation and improving fibrosis-related indicators.

Description

Use of obatoclax in the treatment of metabolic and fibrotic diseases

This application claims priority to Korean Patent Application No. 10-2021-0167564 filed on November 29, 2021, and the entire specification is a reference in this application.

The present invention relates to the use of Obatoclax in the treatment of metabolic diseases and fibrosis, and more particularly, as a novel use of Obatoclax, which exhibits the effect of inhibiting lipid accumulation and improving fibrosis-related indicators, metabolic diseases and fibrosis It relates to disease prevention or treatment use.

Metabolic syndrome is a general term for diseases caused by metabolic disorders in vivo. In general, it is caused by an imbalance of carbohydrates, lipids, proteins, vitamins, electrolytes, and water, and examples thereof include obesity, diabetes, hyperlipidemia, fatty liver, arteriosclerosis, and high blood pressure. Among them, in the case of type 2 diabetes, it is characterized by an increase in resistance to insulin as a diabetes mainly appearing in adulthood. When the insulin receptor itself decreases, or when the sensitivity decreases, or when there is a problem with the second messenger that causes intracellular glycogen synthesis, the sensitivity to insulin decreases. Therefore, type 2 diabetes is called non-insulin dependent diabetes and accounts for 85-90% of diabetes.

In particular, although obesity has become a social issue in terms of appearance and aesthetics, in fact, the most serious problem of obesity is that it can cause serious health risks such as metabolic disease complications such as diabetes and hypertension. A symptom related to such a pathological state of obesity is systemic chronic inflammation that appears in obese individuals. An inflammatory reaction is one of the immune mechanisms occurring in the body, and when it occurs locally, it is an important reaction to defend the body from the invasion of pathogens or viruses from the outside. However, when such an inflammatory response is systemically and chronically excessively activated due to a breakdown in the balance of the body's immune response, it causes disorders in metabolism occurring in the body. The chronic inflammatory response induced by obesity has been identified as the cause of various metabolic syndromes such as diabetes, cardiovascular disease, and arteriosclerosis, and is also the most important factor in defining obesity as a disease. Obesity is simply a cosmetic problem without the occurrence of secondary metabolic syndrome due to chronic inflammatory response, and the World Health Organization recently cited obesity as a disease, citing chronic inflammatory response that can cause secondary metabolic syndrome that significantly reduces quality of life, such as diabetes. has been defined as

On the other hand, fatty liver refers to a state in which fat is abnormally accumulated in hepatocytes, and medically refers to a pathological condition in which the triglyceride content exceeds 5% or more of the total weight of the liver. In general, fatty liver can be divided into alcoholic fatty liver disease (ALD), which is caused by continuous and excessive drinking, and non-alcoholic fatty liver, which has liver tissue findings similar to alcoholic fatty liver, although there is little history of alcohol consumption. there is.

Alcoholic fatty liver disease is common in Korea, and occurs when fat synthesis is promoted in the liver due to alcohol intake and normal energy metabolism is not performed.

Non-alcoholic fatty liver can be caused by causes such as obesity, diabetes, hyperlipidemia, drugs, etc., regardless of drinking. It refers to a wide range of diseases including non-alcoholic steatohepatitis (NASH), advanced fibrosis, and cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is an increase in adult diseases due to high-fat and high-calorie diet intake in modern society, and 20-30% of the adult population in developed countries has nonalcoholic fatty liver disease (NAFLD), among which 2- It is reported that 3% of patients with non-alcoholic steatohepatitis (NASH) are transferred, and in particular, histologically, histological findings of steatohepatitis accompanied by fibrosis and inflammation increase the risk of developing cirrhosis, liver failure, and liver cancer.

Currently, it has been found that steatohepatitis is closely related to obesity, insulin resistance, and type 2 diabetes, but a clear pathogenesis is currently under active research. Insulin resistance, which begins as it accumulates and is associated with obesity and diabetes, is considered to be the main pathogenesis. In addition, it has been reported that lipotoxicity caused by increased free fatty acid (FFA) or cholesterol in hepatocytes, increased inflammatory cytokines, and these receptors play an important role in the process of progressing from fatty liver to steatohepatitis.

On the other hand, fibrosis is a disease in which abnormal production, accumulation, and deposition of extracellular matrix by fibroblasts occurs, and is caused by fibrosis of organs or tissues. Fibrosis is a very fatal disease that causes organ damage. For example, idiopathic pulmonary fibrosis (IPF) occurs as a result of recurrent alveolar epithelial cell damage associated with fibroblast accumulation and myofibroblast differentiation, resulting in irreversible destruction of lung parenchyma tissue and extracellular matrix (ECM). ) is a chronic, progressive, and lethal disease that causes excessive accumulation of However, since there is no effective treatment for fibrosis to date (Fibrogenesis Tissue Repair, 2012, 5(1): 11; N Engl J Med, 2001, 345(7): 517), therapeutic agents that can effectively prevent or treat fibrosis Development is constantly required.

Fibrosis develops as a result of various underlying diseases. Chronic inflammation or tissue damage/remodeling is a typical fibrosis-induced event. Specific disease examples include idiopathic pulmonary fibrosis (IPF), liver fibrosis associated with alcoholic and non-alcoholic liver cirrhosis, renal fibrosis, cardiac fibrosis, and keloid formation resulting from abnormal wound healing [Wynn, T. A. (2004) Nature Reviews. Immunology. 4: 583-594; Friedman, S.L. (2013) Science Translation Medicine. 5(167):1-17]. Additionally, fibrosis is a key pathological feature associated with chronic autoimmune diseases including rheumatoid arthritis, Crohn's disease, systemic lupus erythematosus and scleroderma. Diseases that present a significant unmet medical need include idiopathic pulmonary fibrosis (IPF), scleroderma and nonalcoholic steatohepatitis (NASH) associated liver fibrosis. The increased incidence of NASH-related liver fibrosis is expected to directly parallel that of type 2 diabetes and obesity.

On the other hand, hepatic fibrosis (liver cirrhosis or hepatic fibrosis) or liver cirrhosis (or liver cirrhosis, liver cirrhosis) occurs when liver tissue repeats damage and regeneration, resulting in hepatitis, and progresses from hepatitis to liver fibrosis and from liver fibrosis to cirrhosis. belonging to a disease Liver fibrosis is a fibrosis phenomenon (liver fibrogenesis) that occurs due to the continuous destruction of liver cells and repetitive liver damage. The production of ECM (extracellular matrix) is increased, but the degradation of it is relatively reduced. It progresses to cirrhosis, liver failure or liver cancer. Liver fibrosis is difficult to restore to a normal liver once fibrosis progresses, and it progresses to liver cirrhosis or liver cancer, resulting in a continuously increasing mortality rate. Liver cirrhosis refers to deterioration of liver function by changing normal liver tissue into fibrotic tissue such as regenerative nodules (a phenomenon in which small lumps are formed) due to chronic inflammation. So far, there is no specific treatment for these diseases.

Accordingly, the present inventors have repeatedly conducted intensive research to develop a therapeutic agent that can effectively and safely treat metabolic diseases and fibrotic diseases, and as a result, obatoclax inhibits lipid accumulation and exhibits an improvement effect of fibrosis-related indicators, and this It was found that the same effect is further improved through combination with other drugs, and the present invention was completed.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, an object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases comprising Obatoclax or a pharmaceutically acceptable salt thereof.

In addition, an object of the present invention is to provide a pharmaceutical composition for preventing or treating metabolic diseases consisting essentially of Obatoclax or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating fibrotic disease comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating fibrotic disease comprising Obatoclax or a pharmaceutically acceptable salt thereof.

In addition, another object of the present invention is to provide a pharmaceutical composition for preventing or treating fibrotic disease consisting essentially of Obatoclax or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a use of Obatoclax or a pharmaceutically acceptable salt thereof for preparing a composition for treating metabolic diseases.

Another object of the present invention is to provide a method for treating metabolic diseases comprising administering an effective amount of a composition containing Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof. .

Another object of the present invention is to provide a use of Obatoclax or a pharmaceutically acceptable salt thereof for preparing a composition for treating fibrotic diseases.

Another object of the present invention is to provide a method for treating fibrotic disease comprising administering an effective amount of a composition containing Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof. .

In order to achieve the above object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases comprising Obatoclax or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a pharmaceutical composition for preventing or treating metabolic diseases consisting essentially of Obatoclax or a pharmaceutically acceptable salt thereof.

In order to achieve another object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating fibrotic disease comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient.

In addition, the present invention provides a pharmaceutical composition for preventing or treating fibrotic disease comprising Obatoclax or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a pharmaceutical composition for preventing or treating fibrotic disease consisting essentially of Obatoclax or a pharmaceutically acceptable salt thereof.

In order to achieve another object of the present invention, the present invention provides a use of Obatoclax or a pharmaceutically acceptable salt thereof for preparing a composition for treating metabolic diseases.

In order to achieve another object of the present invention, the present invention is a metabolic activity comprising administering an effective amount of a composition comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof. A method for treating a disease is provided.

In order to achieve another object of the present invention, the present invention provides a use of Obatoclax or a pharmaceutically acceptable salt thereof for preparing a composition for treating fibrotic disease.

In order to achieve another object of the present invention, the present invention provides fibrosis comprising administering an effective amount of a composition comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof. A method for treating a disease is provided.

As used herein, the term "treatment" or "treating" refers to the application or administration of a therapeutic agent, that is, a compound of the present invention (alone or in combination with other pharmaceutical agents) to a patient or HBV infection, HBV infection Treat, cure, alleviate, alleviate, alter, resolve, ameliorate, ameliorate, or improve HBV infection, symptoms of HBV infection, or develop HBV infection from patients at risk of developing symptoms or HBV infection (e.g., diagnosis or disembodied application) It is defined as the application or administration of a therapeutic agent to an isolated tissue or cell line for the purpose of influencing the likelihood of becoming infected. Such treatment can be tailored and modified based on knowledge obtained, inter alia, from the field of genomic pharmacology.

As used herein, the term "prevent" or "prevention" means that, if nothing has happened, there is no development of the disorder or disease, or if there has already been the development of the disorder or disease, there is no further development of the disorder or disease. Also contemplated is one's ability to prevent some or all of the symptoms associated with a disorder or disease.

As used herein, the term "patient", "individual" or "subject" refers to a human or a non-human mammal. For example, non-human mammals include livestock and pets such as ovine, bovine, porcine, canine, feline and murine mammals. Preferably the patient, subject or individual is a human.

As used herein, the terms "effective amount", "pharmaceutically effective amount" and "therapeutically effective amount" refer to a non-toxic sufficient amount of an agent to provide a desired biological result. The result may be a reduction and/or attenuation of a signal, symptom or cause of a disease, or any other desired change in a biological system. An appropriate therapeutic amount for any individual can be determined by one skilled in the art using routine experimentation.

As used herein, the term "pharmaceutically acceptable" means that it does not interfere with the biological activity or properties of a compound and is relatively non-toxic, that is, a substance has an undesirable biological effect or any component of a composition it contains. Refers to a substance, such as a carrier or diluent, that can be administered to an individual without interacting in a detrimental way with the component.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound to be administered prepared from non-toxic acids including pharmaceutically acceptable inorganic acids, organic acids, solvates, hydrates or clathrates thereof. indicate Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, iodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, hexafluorophosphoric acid, citric acid, gluconic acid, benzoic acid, propionic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid. , succinic acid, tartaric acid, amsonic acid, palmic acid, p-toluenesulfonic acid and mesylic acid. Suitable organic acids may be selected, for example, from the aliphatic, aromatic, carboxylic and sulfonic classes of organic acids, such as formic acid, acetic acid, propionic acid, succinic acid, camphorsulfonic acid, citric acid, fumaric acid, gluconic acid, isethionic acid, Lactic acid, malic acid, mucous acid, tartaric acid, para-toluenesulfonic acid, glycolic acid, glucuronic acid, maleic acid, furoic acid, glutamic acid, benzoic acid, atranilic acid, salicylic acid, phenylacetic acid, mandelic acid, emphonic acid (pam acid), Examples include methanesulfonic acid, ethanesulfonic acid, pantothenic acid, benzenesulfonic acid (besylate), stearic acid, sulfanilic acid, alginic acid, and galacturonic acid. Moreover, pharmaceutically acceptable salts include, but are not limited to, alkaline earth metal salts (eg calcium or magnesium), alkali metal salts (eg sodium-dependent or potassium) and ammonium salts. includes

As used herein, the term "pharmaceutically acceptable carrier" refers to a liquid or solid filler, stabilizer, A pharmaceutically acceptable substance, composition or carrier such as a dispersing agent, suspending agent, diluent, additive, thickening agent, solvent or encapsulating material. Typically, these components are carried or transported from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formula, including compounds useful within the present invention, and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose used in pharmaceutical formulations; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc; additives such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; Surfactants; alginic acid; pyrogen-free water; isotonic solution; Ringer's solution; ethyl alcohol; phosphate buffer solution; and other non-toxic, compatible substances. In addition, as used in the present invention, "pharmaceutically acceptable carrier" can be used in combination with the activity of the compound useful in the present invention, and is physiologically acceptable to patients in part or all coating agents, antiviral and antibacterial agents, and absorption delaying agents Include etc. Supplementary active compounds may also be incorporated into the compositions. Further "pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of compounds useful within the present invention. Other additional ingredients that may be included in the pharmaceutical compositions used in the practice of this invention are known in the art.

As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present invention with a pharmaceutically acceptable carrier. A pharmaceutical composition facilitates administration of the compound to a patient or subject. A variety of techniques exist in the art for administering compounds including, but not limited to, intravenous, oral, aerosol, parenteral, ocular, pulmonary and topical administration.

As used herein, the terms "combination therapy" or "in combination" refer to the administration of two or more therapeutic agents to treat the conditions or disorders described herein (ie, metabolic diseases and fibrotic diseases). Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed proportion of the active ingredients. Alternatively, such administration includes co-administration in multiple or separate containers (eg, capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to the desired dosage prior to administration. In addition, such administration includes sequential use of each type of therapeutic agent at about the same time or at different times. In either case, the treatment regimen will provide beneficial effects of the drug combination in the treatment of the conditions or disorders described herein.

Combination therapy can provide a "synergistic effect" and can prove to be "synergistic." That is, the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by using the compounds individually. A synergistic effect occurs when the active ingredients are (1) co-formulated and administered or delivered simultaneously in a combined unit dosage form; (2) when delivered alternately or in parallel as separate dosage forms; or (3) when delivered by some other initiative. When delivered in alternating therapy, a synergistic effect can be obtained when the compounds are administered or delivered sequentially, eg by different injections in separate syringes. Generally, during alternation therapy, effective doses of each active ingredient are administered sequentially, i.e. consecutively, whereas in combination therapy, effective dosages of two or more active ingredients are administered together. Synergistic effect as used herein refers to the action of two therapeutic agents to produce an effect greater than the simple sum of the effects of each drug administered alone. The synergistic effect can be calculated using suitable methods such as, for example, the Sigmoid-Emax equation, the Loewe additive equation, and the median effect equation. Each of the equations mentioned above can be applied to experimental data to generate corresponding graphs that help evaluate the effects of drug combinations. Corresponding graphs related to the above-mentioned equations are concentration-effect curves, isobologram curves, and combination index curves, respectively.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating metabolic diseases comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient.

According to one embodiment of the present invention, the Bcl-2 inhibitor, Obatoclax, has excellent activity to inhibit lipid accumulation in liver cell lines and expression of liver fibrosis markers, thereby preventing the accumulation of lipids in liver cells. It has been confirmed that it can be used very usefully as a preventive or therapeutic agent for metabolic diseases.

In the present invention, the metabolic disease may also be expressed as metabolic syndrome, metabolic disease, etc., and diabetes, obesity, insulin resistance, fatty liver, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia and It can be selected from the group consisting of hypertension. Preferably, the metabolic disease may be fatty liver or non-alcoholic fatty liver disease.

In the present invention, the non-alcoholic fatty liver disease may be selected from the group consisting of non-alcoholic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, and cirrhosis And, most preferably, it may be non-alcoholic steatohepatitis.

Some people with NAFLD can develop a more severe form of NAFLD called non-alcoholic steatohepatitis (NASH), in which accumulation of fat in the liver is associated with inflammation and scarring to varying degrees. In the present invention, the NASH is the NAFLD activity score (NAS), which is the sum of histopathology scores (0 to 3), lobular inflammation scores (0 to 2), and hepatocyte ballooning scores (0 to 2) of liver biopsies for steatosis. Can be defined within the NAFLD scope by

In one aspect of the present invention, the pharmaceutical composition comprises an additional drug selected from the group consisting of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and GABA-transaminase inhibitors can include

The NNRTI acts by directly binding to the enzyme at a site other than the nucleoside binding component, causing allosteric inhibition of the transcription enzyme. That is, NNRTIs bind to reverse transcriptase non-competitively and act as a mechanism to change the structure to prevent DNA binding, and are used as a treatment for HIV-1 infection.

Non-limiting examples of the NNRTI may include etravirine, nevirapine, rilpivirine, delavirdine, efavirenz and doravirine, , preferably etravirine.

The GABA transaminase inhibitors of the present invention are typically competitive inhibitors of GABA transaminase, and are typically also structural analogs or isomers of GABA, but additionally conformationally such as sterically hindered moieties or additional linkages, particularly ring linkages. may be constrained. GABA transaminase acts to increase the concentration of GABA in the body by reducing the degradation of GABA.

Non-limiting examples of the GABA transaminase inhibitor include cycloserine, ethanolamine-O-sulfate, gamma-acetylenic-GABA, and vigabatrin ( vigabatrin), aminooxyacetic acid, valproate, and phenylethylidenehydrazine, and preferably cycloserine.

In one aspect of the invention, the obatoclax; And one or more drugs selected from the group consisting of NNRTIs and GABA transaminase inhibitors may be used as a combination therapy or as a combination agent to treat metabolic diseases.

Specifically, Obatoclax and NNRTI; obatoclax and GABA transaminase inhibitors; And any one or more combination therapies or combination agents selected from the group consisting of Obatoclax, NNRTI, and GABA transaminase inhibitors may exhibit a synergistic effect in preventing or treating metabolic diseases.

In this case, each component included in the combination preparation may be formulated for use separately, simultaneously or sequentially. That is, in the case of sequential administration, the combination preparation may be administered in two or more administrations. Concomitant administration can include co-administration using separate formulations or a single pharmaceutical formulation, as well as sequential administration in either order.

In the present invention, when Obatoclax and an additional drug are used as a combination therapy or combination drug, these combination drugs may be administered in combination at a molar ratio of 1:0.01 to 500, preferably a molar ratio of 1:1 to 10. can be administered concomitantly. When the obatoclax is used as a combination therapy or combination preparation with two or more drugs, these combination drugs may be administered in combination at a molar ratio of 1:0.01 to 500:0.01 to 500.

The present invention also relates to obatoclax or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating metabolic diseases comprising at least one selected from the group consisting of etravirine, cycloserine, and pharmaceutically acceptable salts thereof as an active ingredient.

Specifically, obatoclax and etravirine; obatoclax and cycloserine; And any one or more combination therapies or combination agents selected from the group consisting of obatoclax, etravirine, and cycloserine may exhibit a synergistic effect in preventing or treating metabolic diseases.

The pharmaceutical composition according to the present invention may contain obatoclax alone or may be formulated in a suitable form together with a pharmaceutically acceptable carrier, and may further contain an excipient or diluent. In the above, 'pharmaceutically acceptable' refers to a non-toxic composition that is physiologically acceptable and does not cause allergic reactions such as gastrointestinal disorders, dizziness, etc., or similar reactions when administered to humans.

A pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration.

Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like.

In addition, various drug delivery materials used for oral administration may be included. In addition, the carrier for parenteral administration may include water, suitable oil, saline, aqueous glucose and glycol, and the like, and may further include a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium bisulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol.

The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifier, a suspending agent, and the like in addition to the above components. Reference may be made to other pharmaceutically acceptable carriers and agents known in the art.

In the present invention, the content of the composition is not significantly limited depending on the purpose or aspect of use, for example, 0.01 to 99% by weight, preferably 0.5 to 50% by weight, more preferably 1 to 30% by weight based on the total weight of the composition. weight percent. In addition, the pharmaceutical composition according to the present invention may further include additives such as pharmaceutically acceptable carriers, excipients or diluents in addition to active ingredients. The pharmaceutical composition of the present invention may include 0.1 to 99.9% by weight of the composition containing obatoclax and 99.9% to 0.1% by weight of the carrier.

The pharmaceutical composition according to the invention may include a pharmaceutically effective amount of the compound alone or may further include one or more pharmaceutically acceptable carriers. The pharmaceutical composition of the present invention may be administered to a patient as a single dose, or may be administered by a fractionated treatment protocol in which multiple doses are administered over a long period of time. In the above, the pharmacologically effective amount refers to an amount that exhibits a higher response than that of the negative control group, and preferably refers to an amount sufficient to treat or prevent metabolic diseases or fibrotic diseases. An effective amount of the composition according to the present invention may be 0.001 to 1000 mg/kg b.w./day, preferably 1 to 2000 mg/kg b.w./day, but is not limited thereto. However, the pharmaceutically effective amount may be appropriately changed depending on various factors such as the disease and its severity, the patient's age, weight, health condition, sex, administration route and treatment period.

The composition of the present invention can be administered to mammals including humans by any method. For example, it can be administered orally or parenterally. Parenteral administration methods include, but are not limited to, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual or rectal administration can be

The pharmaceutical composition of the present invention may be formulated into a formulation for oral administration or parenteral administration according to the administration route as described above.

In the case of preparations for oral administration, the composition of the present invention may be formulated into powders, granules, tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, etc. using a method known in the art. can For example, preparations for oral use may be obtained by combining the active ingredient with a solid excipient, which is then milled and, after adding suitable auxiliaries, processed into a mixture of granules to obtain tablets or dragees. Examples of suitable excipients include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol and maltitol, starches including corn starch, wheat starch, rice starch and potato starch, cellulose, Celluloses including methyl cellulose, sodium carboxymethylcellulose and hydroxypropylmethyl-cellulose, and the like, fillers such as gelatin, polyvinylpyrrolidone, and the like may be included. In addition, cross-linked polyvinylpyrrolidone, agar, alginic acid or sodium alginate may be added as a disintegrant, if desired.

Furthermore, the pharmaceutical composition of the present invention may further include an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifier, and a preservative.

In the case of preparations for parenteral administration, they may be formulated in the form of injections, creams, lotions, external ointments, oils, moisturizers, gels, aerosols, and nasal inhalants by methods known in the art. These formulations are described in prescriptions generally known to all pharmaceutical chemists.

The total effective amount of the composition of the present invention can be administered to the patient in a single dose or by a fractionated treatment protocol in which multiple doses are administered over a long period of time. The pharmaceutical composition of the present invention may vary the content of the active ingredient according to the severity of the disease. Preferably, the preferred total dose of the pharmaceutical composition of the present invention may be about 0.01 to 10,000 mg, most preferably 0.1 to 500 mg per patient body weight per day. However, the dosage of the pharmaceutical composition is determined by considering various factors such as the formulation method, administration route and number of treatments as well as the patient's age, weight, health condition, sex, severity of disease, diet and excretion rate Therefore, considering this point, those skilled in the art will be able to determine an appropriate effective dosage of the composition of the present invention. The pharmaceutical composition according to the present invention is not particularly limited in its formulation, administration route and administration method as long as it exhibits the effects of the present invention.

The present invention also provides a pharmaceutical composition for preventing or treating fibrotic disease comprising obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient.

In the present invention, the fibrotic disease is also called fibrosis, and is a chronic and progressive disease characterized by excessive accumulation of extracellular matrix (ECM) leading to hardening and/or scarring of related tissues. It develops through complex interactions of cells, extracellular matrix, cytokines, and growth factors. Other cell types include resident mesenchymal cells (fibroblasts and myofibroblasts) and ECM-producing cells derived from epithelial and endothelial cells (through a process called epithelial- and endothelial-mesenchymal transition), and local or bone marrow-derived stem cells (fibroblasts). ), etc. Fibroblasts have long been considered as the major cell type involved in normal wound healing and as important effector cells in fibrogenesis. They are highly synthetic to collagen and other ECM components, and are also characterized by de novo expression of α-smooth muscle actin (α-SMA). The presence of myofibroblasts in fibrotic lesions in animal models of fibrosis correlates with the onset of active fibrosis, and the persistence and localization of fibrotic lesions in humans is associated with disease progression. Myofibroblasts also display an enhanced migration phenotype and can release multiple mediators of profibrosis.

In the present invention, the type of fibrotic disease is not particularly limited, and is caused by chronic inflammation or tissue damage/remodeling, etc., and is a progressive disease that leads to hardening and/or scarring of related tissues due to excessive accumulation of extracellular matrix (ECM). Any disease can be included. Non-limiting examples of the fibrotic disease may include pulmonary fibrosis, liver fibrosis, skin fibrosis, renal fibrosis, pancreatic fibrosis, systemic sclerosis and cardiac fibrosis.

The lung fibrosis is a serious medical condition involving scarring of lung tissue. These symptoms occur when the alveoli and interstitial tissue of the lungs become inflamed and develop scars in the tissue in an attempt to repair itself. Pulmonary fibrosis involves progressive exchange of fibrotic tissue (fibrous scar) with normal lung parenchyma.

Pulmonary fibrosis is characterized by chronic inflammatory processes (sarcomatosis, Wegener's granulomatous disease), infections, environmental agents (exposure to asbestos, silica, certain gases), exposure to ionizing radiation (e.g. radiation therapy to treat tumors in the chest), and chronic conditions. (lupus), and certain medications (eg amiodarone, bleomycin, pingyangmycin, busulfan, methotrexate, and nitrofurantoin).

In a condition known as hypersensitivity pneumonitis, fibrosis of the lungs may develop after a high immune response to inhaled organic dust or industrial chemicals. These symptoms mostly result from inhalation of dust contaminated with bacteria, fungi, or animal products.

The liver fibrosis or hepatic fibrosis is a process of excessive accumulation of extracellular matrix proteins (including collagen) and subsequent scar formation that occurs in most chronic liver diseases. Liver fibrosis that progresses over time results in cirrhosis. Cirrhosis is the final stage of chronic liver disease and is generally irreversible with poor long-term prognosis. At an advanced stage, the only option is a liver transplant. The risk of liver cancer is significantly increased with cirrhosis, and cirrhosis can be seen as a precancerous condition (hepatocellular carcinoma). In fact, cirrhosis and liver cancer are among the top 10 causes of death worldwide. Thus, there is a need for effective treatment of liver fibrosis and subsequent cirrhosis. Unfortunately, there are few treatment options available, and most treatment consists of addressing the causes and/or symptoms of cirrhosis.

A limited number of clinical trials are ongoing with candidate drugs that specifically address the inhibition or retardation of fibrosis in the liver. However, these trials target specific liver diseases, such as non-alcoholic steatohepatitis (NASH).

The skin fibrosis or epidermal fibrosis is excessive scarring of the skin and results from a pathological wound healing response. There are a wide range of fibrotic skin diseases: scleroderma, nephrogenic dermatosis, mixed connective tissue disease, sclerosing myxedema, sclerotic hydrocele, and eosinophilic fasciitis. Exposure to chemical or physical agents (mechanical trauma, burns) is also a potential cause of fibrotic skin disease. Skin fibrosis can be driven by immune, autoimmune and inflammatory mechanisms. The balance of collagen production and degradation in fibroblasts plays an important role in the pathophysiological process of skin fibrosis. Certain cytokines such as transforming growth factor-β (TGB-β) and interleukin-4 (IL-4) promote wound healing and fibrosis, while interferon-γ (IFN-γ) and tumor necrosis factor-α ( Others, such as TNF-α), are anti-fibrotic. Fibroblasts in normal skin are quiescent. They control the amount of connective tissue proteins and have low proliferative activity. After skin injury, these cells are activated, ie they express α-smooth muscle actin (α-SMA) and synthesize large amounts of connective tissue proteins. Activated cells are often called myofibroblasts.

scleroderma refers to skin fibrosis; Sclera = hard and dermal skin. However, dermal fibrosis can have a significant impact on health outcomes, particularly when it is part of systemic scleroderma. The latter refers to connective tissue diseases of autoimmune etiology. Restricted cutaneous scleroderma is limited to the skin of the face and feet, whereas diffuse cutaneous scleroderma covers more skin and may progress to the visceral organs.

The renal fibrosis means excessive proliferation of cells, hardening of tissues and scars. Renal fibrosis can result from renal failure and catheterization, eg dialysis following peritoneal and vascular access fibrosis. Renal fibrosis can also result from nephropathy such as glomerular disease (eg glomerulosclerosis, glomerulonephritis), chronic renal failure, acute renal failure, end-stage renal disease and renal failure. Regardless of etiology, all patients with chronic kidney disease exhibit a gradual decline in renal function over time. Fibrosis, so-called scarring, is a major cause of the pathophysiology. Fibrosis involves excessive accumulation of extracellular matrix (composed primarily of collagen), usually resulting in loss of function when normal tissue is replaced by scar tissue. This process is often irreversible and essentially leads to end-stage renal failure, a condition requiring lifelong dialysis or kidney transplantation.

The cardiac fibrosis, a hallmark of heart disease, is thought to contribute to sudden cardiac death, ventricular arrhythmias, left ventricular (LV) dysfunction, and cardiac disorders. Cardiac fibrosis is characterized by disproportionate accumulation of fibrotic collagen, inflammation, increased workload, hypertrophy, and stimulation by a number of hormones, cytokines, and growth factors that occur after cardiomyocyte death.

Cardiac fibrosis can also refer to abnormal thickening of heart valves due to disproportionate proliferation of cardiac fibroblasts, but more generally refers to proliferation of fibroblasts in the heart muscle. Fibrous cells normally secrete collagen and function to provide structural support for the heart. When overly activated, this process causes thickening and fibrosis of the valves, at which time white tissue not only builds the tricuspid valve, but also occurs in the pulmonary valve. Concentration and loss of flexibility can eventually lead to valve failure and right-sided heart failure.

Chronic pancreatitis (CP), which causes pancreatic fibrosis, is a progressive inflammatory disease of the pancreas characterized by irreversible morphological changes and progressive fibrotic replacement of the gland. In parenchymal fibrosis, loss of exocrine and endocrine function occurs. The main symptoms of CP are abdominal pain and indigestion. Extremely, the pancreas may be enlarged or atrophied with or without cysts or calcifications or tumors. The tube may be dilated, irregular or constricted. The major pathological features include irregular and non-uniform loss of lobular tissue, chronic inflammation, ductal changes and fibrosis. Gene mutations (including but not limited to cystic fibrosis, cationic trypsinogen gene, CFTR gene mutation in idiopathic acute and chronic pancreatitis, pancreatic secretory trypsin inhibitor gene, chymotrypsinogen C gene, calcium sensing receptor gene, α- 1 including antitrypsin deficiency), metabolic (alcohol, tobacco smoking, hypercalcemia, hyperlipidemia, chronic renal failure), environmental factors (micronutrient deficiencies (nutritional factors such as zinc, copper and selenium; also post-irradiation exposure), obstructive ( tumor), ischemic (vascular disease)) and autoimmune diseases, or is the final manifestation of a complex pathogenic mechanism associated with primary sclerosing bile duct flames, Sjogren's syndrome, primary biliary disorders and type 1 diabetes mellitus.

In such various fibrosis, the composition containing obatoclax according to the present invention suppresses the fibrotic reaction by reducing the amount of procollagen alpha 1 in each tissue or cell, and this effect is a non-nucleoside reverse transcriptase Synergistic effects may occur when used in combination with one or more drugs selected from the group consisting of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and GABA-transaminase inhibitors.

The present invention also relates to obatoclax or a pharmaceutically acceptable salt thereof; And it provides a pharmaceutical composition for preventing or treating fibrotic disease comprising at least one selected from the group consisting of etravirine, cycloserine and pharmaceutically acceptable salts thereof as an active ingredient.

The present invention provides a use of Obatoclax or a pharmaceutically acceptable salt thereof for preparing a composition for treating metabolic diseases.

The present invention provides a method for treating metabolic diseases comprising administering an effective amount of a composition containing Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

The present invention provides a use of Obatoclax or a pharmaceutically acceptable salt thereof for preparing a composition for treating fibrotic disease.

The present invention provides a method for treating fibrotic disease comprising administering an effective amount of a composition containing Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

The 'effective amount' of the present invention refers to an amount that exhibits an effect of improving, treating, detecting, diagnosing, or suppressing or reducing a metabolic disease or fibrotic disease when administered to a subject, and the 'subject' refers to an animal, preferably may be mammals, especially animals including humans, and may be cells, tissues, organs, etc. derived from animals. The subject may be a patient in need of the effect.

The 'treatment' of the present invention refers comprehensively to improving a metabolic disease or a fibrotic disease or a symptom caused by the disease, which may include curing, substantially preventing, or improving the condition of the disease, , including, but not limited to, alleviating, curing or preventing one or most of the symptoms resulting from the disease.

In this specification, the term "comprising" is used in the same meaning as "including" or "characterized by", and in the composition or method according to the present invention, specifically mentioned It does not exclude additional components or method steps not specified. Also, the term "consisting of" means excluding additional elements, steps or components not separately described. The term "essentially consisting of" means that in the scope of a composition or method, in addition to the described materials or steps, materials or steps that do not substantially affect the basic characteristics thereof may be included.

The composition of the present invention containing obatoclax is very effective in inhibiting lipid accumulation and fibrosis in liver cells, and these effects are non-nucleoside reverse transcriptase inhibitors (Non-nucleoside reverse transcriptase inhibitors, NNRTI) And GABA transaminase (GABA-transaminase) inhibitors can be used in combination with one or more drugs selected from the group consisting of a synergistic effect can be very useful for the development of metabolic diseases and fibrotic diseases prevention or treatment.

1 shows the results of evaluating the lipid accumulation inhibitory activity of these drugs by treating human liver cell line HepG2 with palmitic acid (PA) to induce lipid accumulation, and then treating them with etravirine or obatoclax.

Figure 2 shows the human liver cell line HepG2 treated with palmitic acid (PA) culture medium treated with human hepatic stellate cells LX-2 together with etravirine or obatoclax, and the ability of these drugs to inhibit the expression of the fibrosis marker aSMA is the result of evaluation.

Figure 3 is a result of evaluating the cytotoxicity of etravirine, obatoclax, or a combination thereof in human hepatic stellate cells, LX-2, by MTT assay.

Figure 4 shows the amount of procollagen alpha 1 secreted into the culture medium after treating non-alcoholic steatohepatitis fibrosis-induced human hepatic stellate cells LX-2 with etravirine, obatoclax, or a combination thereof at a Cmax concentration. This is the result confirmed by ELISA assay.

Figure 5 shows the treatment of non-alcoholic steatohepatitis fibrosis-induced human hepatic stellate cells LX-2 with etravirine, obatoclax, or a combination thereof at a Cmax concentration, and then intracellular fibrosis marker genes (Col1A1, fibronectin and This is the result of confirming the expression change of Col4A1) by qPCR.

Figure 6 shows the results of AST and ALT measurements according to the combined administration of obatoclax alone or etravirine and obatoclax to a non-alcoholic steatohepatitis animal model (CDA-HFD).

7 is a result of liver tissue weight measurement according to the combined administration of obatoclax alone or etravirine and obatoclax to a non-alcoholic steatohepatitis animal model (CDA-HFD).

Figure 8 is a NAFLD activity score according to the combined administration of obatoclax alone or etravirine and obatoclax to a non-alcoholic steatohepatitis animal model (CDA-HFD).

9 is a Steatosis score according to obatoclax alone or combined administration of etravirine and obatoclax to a non-alcoholic steatohepatitis animal model (CDA-HFD).

Figure 10 is a lobular inflammation score according to the combined administration of obatoclax alone or etravirine and obatoclax to a non-alcoholic steatohepatitis animal model (CDA-HFD).

11 is a fibrosis score according to obatoclax alone or combined administration of etravirine and obatoclax to a non-alcoholic steatohepatitis animal model (CDA-HFD).

12 shows hematoxylin & eosin (H&E) and Psrius red (PSR) staining of liver tissue sections following the administration of obatoclax alone or etravirine and obatoclax in a non-alcoholic steatohepatitis animal model (CDA-HFD) It is a picture.

Hereinafter, the present invention will be described in detail by the following examples. However, the following examples are only for illustrating the present invention, and the present invention is not limited thereto.

Example 1. Lipid accumulation inhibitory activity in liver cells

HepG2 cell line, a human hepatocyte, was treated with 400 uM of palmitic acid and then treated with obatoclax or etravirine at a concentration of 2.5 uM. After 24 hours, the amount of neutral fat accumulated in the cells was measured by Oil-red O staining.

As a result, as shown in Figure 1, it was confirmed that lipid accumulation in liver cells was significantly inhibited in the obatoclax or etravirine-treated group compared to the untreated control group.

Example 2. Efficacy of inhibiting liver fibrosis

Human hepatocyte HepG2 cell line was treated with 400 uM of palmitic acid for 24 hours (HepG2-PACM), and human hepatic stellate cell LX-2 cells were treated with obatoclax or etravirine (2.5 uM). After 24 hours, fibrosis marker aSMA was stained and quantified in LX-2 cells.

As a result, as shown in FIG. 2, it was confirmed that the expression of the fibrosis marker aSMA in liver cells was suppressed in the obatoclax or etravirine-treated group compared to the untreated control group.

Example 3. Cytotoxicity evaluation

In Examples 1 and 2, obatoclax and etravirin, which are excellent lipid accumulation inhibitory and fibrosis inhibitory drugs, were treated alone or concurrently at the Cmax concentration in blood at the licensed dose to the LX-2 cell line, which is a human hepatic stellate cell. After 48 hours and 72 hours, the cell growth rate was measured by MTT assay.

The approved dosage and usage of etravirine is oral administration of 200 mg twice daily for adults, and the average plasma Cmax at this time is 401 ng/mL (minimum 255 mL ~ maximum 1190 ng/mL). When this is converted into a molar concentration, it is about 0.92 uM (minimum 0.56 uM ~ maximum 2.74 uM) (NCT01121809; J Antimicrob Chemother . 2012 Mar; 67 (3): 681-4). In this experiment, cells were treated with 1 uM of etravirine.

Obatoclax is an FDA-approved drug, and the dosage and regimen allowed in phase 1/2 clinical trials are 20, 28, and 40 mg/m ² intravenous administration over 3 hours (NCT00600964; Blood . 2009 Jan 8; 113 (2): 299 -305). The average plasma Cmax at this time was 77.9 ng/mL, 72.9 ng/mL, and 92.6 ng/mL, respectively, which are about 188 nM, 176 nM, and 224 nM when converted into molar concentrations. In this experiment, 200 nM of obatoclax was treated.

As a result, as shown in FIG. 3, no cytotoxicity was observed in the groups treated with etravirine alone, obatoclax alone, and the combination thereof.

Example 4. Fibrosis inhibition ability at Cmax concentration

LX-2 cell line, a human hepatic stellate cell, was treated with a culture solution (500 uM) mixed with oleic acid and palmitic acid in a ratio of 2:1 and TGF beta (5 ng/mL) to induce fibrosis in non-alcoholic steatohepatitis. did

Simultaneously with the induction, etravirine (1 uM) and obatoclax (200 nM) were treated alone or simultaneously at the Cmax concentration in blood at the approved dose. After 24 hours, the expression level of intracellular fibrosis genes (Col1A1, Col4A1 and Fibronectin) was analyzed by qPCR, and the amount of procollagen alpha 1 secreted into the culture medium after 48 hours was measured by ELISA technique.

As a result, as shown in Figure 4, the fibrosis reaction was reduced by about 76% by etravirine treatment alone, and the fibrosis reaction was reduced by about 34% by Obatoclax alone treatment. When the two drugs were simultaneously treated, it was confirmed that the fibrosis reaction was inhibited by about 98%.

In addition, as shown in Figure 5, the expression of the fibrosis gene Col1A1 was reduced by 26%, respectively, by etravirine treatment alone. Expression of the fibrosis gene Col4A1 and fibronectin were reduced by 50% and 21%, respectively, by Obatoclax alone. Co-treatment with etravirine and obatoclax reduced the gene expression of Col1A1, Col4A1 and Fibronectin by 49%, 72% and 45%, respectively.

Example 5. Oral drug administration experiment using non-alcoholic steatohepatitis animal model

Example 5-1: Preclinical test preparation and implementation

C57/BL/6 Mice with special feed CDA-HFD (L-Amino Acid Rodent Diet With 60 kcal% Fat, No Added Choline and 0.1% Methionine (Cat No: A06071302)) in feeding period for 6 weeks and freely consumed Non-alcoholic steatohepatitis and liver fibrosis models were made, and the normal group was freely fed a Matched control diet (L-Amino Acid Diet with 10 kcal% Fat with Methionine and Choline (Cat No: A06071314)). Mice with non-alcoholic steatohepatitis were maintained on the CDA-HFD diet, and obeticholic acid (OCA) 30 mg/kg/day and obatoclax (OBX) low concentration 0.2 mg/kg, respectively. /day, obatoclax high concentration 1 mg/kg/day was intravenous administration daily for 3 weeks, and obatoclax low concentration 20 mg/kg/day and obatoclax low concentration 0.2 mg/kg/day were used together. After oral administration and intravenous injection, respectively, the symptoms were measured and recorded on the 21st day. The composition of each test group is shown in Table 1 below. (N=10/group, G1: Matched control diet, G2: CDA-HFD, G3: CDA-HFD + OCA, G4: CDA-HFD + CDA-HFD + Obatoclax (0.2 mpk, IV), G5: CDA-HFD + Obatoclax (1 mpk, IV), G6: CDA-HFD + Etravirine + Obatoclax (20 mpk, PO + 0.2 mpk, IV)

Symptomatic observation was performed at least twice a day for all animals. Records were maintained for subjects exhibiting clinical symptoms. If a dead animal occurred during the test period, an autopsy was performed according to the contents discussed with the test client. Grouping was performed at week 6 based on the results of blood glucose, ALT (FUJI, #3250), and AST (FUJI, #3150) items at week 5 after model induction. Blood glucose was measured using a blood glucose meter (Diatech Korea, Auto-chek plus), and ALT and AST were analyzed using a fully automatic dry biochemical analyzer (FUJI, Dri-Chem NX700ie).

In the case of the liver, the total liver tissue was weighed and photographed. Among them, the left lobe was fixed in 10% neutral buffered formalin, and H&E staining, slide scan, and PSR staining were performed, and NAS (NAFLD activity score) and FS (NASH fibrosis stage) analysis were performed. The analysis criteria of NAS and FS are shown in Table 2 below.

The results of this experiment were analyzed using parametric multiple comparison procedures, assuming normality of the data. If the results of one-way ANOVA were significant, a post hoc test was performed using Dunnett's multiple comparison test. Statistical analysis was performed using Prism 8.4.3 (GraphPad Software Inc., San Diego, CA, USA), and a p value of less than 0.05 was determined to be statistically significant.

Example 5-2: Blood biochemical analysis (AST, ALT)

As shown in FIG. 6, as a result of blood biochemical analysis, AST was significantly higher in all test groups (G2-G6) compared to 88.93 ± 19.47 IU / L in the G1 Matched control diet group (p <0.01). ALT was also significantly higher in all test groups (G2~G6) compared to 47.15 ± 18.73 IU/L in the G1 Matched control diet group (p<0.01). Compared to the G2 CDA-HFD group, there was no significant difference in AST/ALT from other test groups except for the G1 group. The blood biochemical analysis results of each test group are summarized in Table 3 below.

Example 5-3: Liver Tissue Weight

As shown in FIG. 7, the absolute weight of liver tissue of 1.60 ± 0.25 g of the G1 Matched control diet group was not significantly different from that of the other test groups (G2 to G8). Compared to the G2 CDA-HFD group of 1.82 ± 0.27 g, there was no significant difference in tissue absolute weight between the other test groups except for the G1 group.

As a result of measuring the relative weight of liver tissue, G2 CDA-HFD group 7.58 ± 0.92%, G3 CDA-HFD + OCA group 7.71 ± 1.26%, G4 CDA-HFD + Obato group compared to G1 Matched control diet group 4.79 ± 0.36% Clarks (0.2 mpk, IV) group 7.27 ± 1.28%, G5 CDA-HFD + Obatoclax (1 mpk, IV) group 7.13 ± 0.97% and G6 CDA-HFD + Etravirine + Obatoclax (20 mpk, PO + 0.2 mpk, IV) group 7.80 ± 1.48% significantly higher relative weight of liver tissue was confirmed (p <0.01). And compared to the G2 CDA-HFD group (7.58 ± 0.92%), there was no significant difference in tissue relative weight between the other test groups except for the G1 group. The liver tissue weights of each test group are summarized and shown in Table 4 below.

Example 5-4: Clinical Signs and Necropsy Findings

As a result of observing general symptoms daily, no abnormalities were observed during the test period. In addition, as a result of the autopsy at the end of the test, no abnormal lesions were identified in major organs except the liver.

Example 5-5: NAFLD activity score (NAS)

As a result of NAS analysis of liver tissue L1A, it was significantly higher in all test groups (G2 ~ G6) than the G1 Matched control diet group, 0.00 ± 0.00 score (p <0.01). G2 CDA-HFD group 3.70 ± 1.16 score, G3 CDA-HFD + OCA group 1.60 ± 0.84 score, G4 CDA-HFD + Obatoclax (0.2 mpk, IV) group 2.33 ± 0.71 score, G5 CDA-HFD + OVA The Toclax (1 mpk, IV) group scored 1.70 ± 0.82, and the G6 CDA-HFD + Etravirine + Obatoclax (20 mpk, PO + 0.2 mpk, IV) group scored 1.70 ± 0.95, which was significantly lower. (p<0.01, Figures 8 to 10 and Table 5).

As a result of NAS analysis of liver tissue L1B, it was significantly higher in all test groups (G2-G6) than the G1 Matched control diet group, 0.00 ± 0.00 score (p<0.01). G2 CDA-HFD group 3.30 ± 0.95 score, G3 CDA-HFD + OCA group 1.40 ± 0.70 score, G4 CDA-HFD + Obatoclax (0.2 mpk, IV) group 2.22 ± 0.67 score, G5 CDA-HFD + OVA Toclax (1 mpk, IV) group 1.50 ± 0.71 score, G6 CDA-HFD + Etravirine + Obatoclax (20 mpk, PO + 0.2 mpk, IV) group 1.40 ± 0.70 score, which was measured as significantly lower. (p<0.01 or p<0.05, Figures 8 to 10 and Table 6).

Example 5-6: Fibrosis stage (FS)

As a result of the FS analysis of liver tissue L1A, as shown in FIGS. 11 and 12, the G2 CDA-HFD group was analyzed as the highest stage as stage 3, the G3 CDA-HFD + OCA group, and the G4 CDA-HFD + Obatoclac The S (0.2 mpk, IV) group was analyzed as stage 2. The G5 CDA-HFD + Obatoclax (1 mpk, IV) group and the G6 CDA-HFD + Etravirine + Obatoclax (20 mpk, PO + 0.2 mpk, IV) group were classified as stage 1c, the lowest stage. analyzed. The FS of each test group is shown in Table 7 below.

In conclusion, the dose-dependent effect of obatoclax on fatty liver improvement and hepatic fibrosis inhibition was confirmed in the non-alcoholic steatohepatitis model induced by the CDA-HFD feed. In particular, it was confirmed that the NAS and FS levels were further improved when etravirine and obatoclax were co-administered compared to the low-concentration Obatoclax administration alone, compared to the Obatoclax high-concentration administration group. From this, it can be inferred that combined administration of obatoclax and etravirine and obatoclax is possible as a treatment for non-alcoholic steatohepatitis.

The composition of the present invention containing obatoclax is very effective in inhibiting lipid accumulation and fibrosis in liver cells, and these effects are non-nucleoside reverse transcriptase inhibitors (Non-nucleoside reverse transcriptase inhibitors, NNRTI) And GABA transaminase (GABA-transaminase) inhibitors can be used in combination with one or more drugs selected from the group consisting of synergistic effects, which can be used very usefully in the development of preventive or therapeutic agents for metabolic diseases and fibrotic diseases, so industrial applicability this is very high

Claims (17)

1. A pharmaceutical composition for preventing or treating metabolic diseases comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient.
2. The pharmaceutical composition according to claim 1, wherein the metabolic disease is selected from the group consisting of diabetes, obesity, insulin resistance, fatty liver, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia and hypertension. .
3. The method of claim 2, wherein the non-alcoholic fatty liver disease is selected from the group consisting of non-alcoholic steatosis, non-alcoholic steatohepatitis, fibrosis, and cirrhosis. A pharmaceutical composition, characterized in that.
4. The method of claim 1, comprising at least one additional drug selected from the group consisting of Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and GABA-transaminase inhibitors. Characterized by the pharmaceutical composition.
5. The method of claim 4, wherein the NNRTI is etravirine, nevirapine, rilpivirine, delavirdine, efavirenz, doravirine and their A pharmaceutical composition, characterized in that selected from the group consisting of pharmaceutically acceptable salts.
6. The method of claim 4, wherein the GABA transaminase inhibitor is cycloserine, ethanolamine-O-sulfate, gamma-acetylenic-GABA, vigabatrin (vigabatrin), aminooxyacetic acid (aminooxyacetic acid), valproate (valproate), phenylethylidenehydrazine (phenylethylidenehydrazine) and pharmaceutically acceptable salts thereof, characterized in that selected from the group consisting of a pharmaceutical composition.
7. The method of claim 4, wherein the obatoclax; And non-nucleoside reverse transcriptase inhibitors (Non-nucleoside reverse transcriptase inhibitors, NNRTIs), GABA transaminase inhibitors (GABA-transaminase inhibitors), or combinations thereof are simultaneously, individually or sequentially administered in combination. enemy composition.
8. The pharmaceutical composition according to claim 4, wherein the obatoclax and the additional drug are co-administered in a molar ratio of 1:0.01 to 500.
9. obatoclax or a pharmaceutically acceptable salt thereof; And Etravirine, cycloserine and a pharmaceutical composition for preventing or treating metabolic diseases comprising at least one member selected from the group consisting of pharmaceutically acceptable salts thereof as an active ingredient.
10. A pharmaceutical composition for preventing or treating fibrotic disease comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient.
11. The pharmaceutical composition according to claim 10, wherein the fibrotic disease is selected from the group consisting of pulmonary fibrosis, liver fibrosis, skin fibrosis, kidney fibrosis, pancreatic fibrosis, systemic sclerosis and cardiac fibrosis.
12. 11. The method of claim 10, characterized in that it comprises an additional drug selected from the group consisting of Non-nucleoside reverse transcriptase inhibitors (NNRTIs) and GABA-transaminase inhibitors. A pharmaceutical composition to.
13. obatoclax or a pharmaceutically acceptable salt thereof; and etravirine, cycloserine, and a pharmaceutical composition for preventing or treating fibrotic disease comprising at least one member selected from the group consisting of pharmaceutically acceptable salts thereof as an active ingredient.
14. Use of Obatoclax or a pharmaceutically acceptable salt thereof for preparing a composition for treating metabolic diseases.
15. A method for treating a metabolic disease comprising administering an effective amount of a composition comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.
16. Use of Obatoclax or a pharmaceutically acceptable salt thereof for preparing a composition for the treatment of fibrotic diseases.
17. A method for treating fibrotic disease comprising administering an effective amount of a composition comprising Obatoclax or a pharmaceutically acceptable salt thereof as an active ingredient to a subject in need thereof.

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