Caspase inhibitor for preventing or treating heart diseases

Abstract

One aspect of the present invention relates to a pharmaceutical composition for preventing or treating heart diseases, the composition comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof. The pharmaceutical composition has an excellent effect of inhibiting apoptosis and inflammatory activity, and thus can be used for preventing or treating heart diseases, such as cardiac hypertrophy, caused by atrial fibrillation, heart failure, or hypertension.

Description

Caspase inhibitors for the prevention or treatment of heart disease

[0001] The present invention relates to a method for preventing or treating heart disease comprising administering a caspase inhibitor or a pharmaceutically acceptable salt thereof to a subject, a pharmaceutical composition for preventing or treating heart disease comprising the caspase inhibitor or a pharmaceutically acceptable salt thereof, a kit comprising the caspase inhibitor or a pharmaceutically acceptable salt thereof or the pharmaceutical composition, the use of the caspase inhibitor or a pharmaceutically acceptable salt thereof for preventing or treating heart disease, or the use for manufacturing a medicament for preventing or treating heart disease. The caspase inhibitor may be a pan-caspase inhibitor or a selective caspase inhibitor.

[0002] Inflammation is widely recognized as an important risk factor for cardiovascular disease and is associated with various cardiovascular diseases such as coronary artery disease, stroke, arrhythmia, and heart failure.

[0003] Atrial fibrillation, in particular, is a common arrhythmia and can lead to serious side effects, such as stroke. It is a critical condition requiring management, and inflammation is identified as a key risk factor. Furthermore, heart failure, caused by functional or structural abnormalities of the heart, is also a critical condition requiring management, with hospitalization and mortality rates increasing with the aging population. Inflammation is also known to be a major risk factor.

[0004] However, despite the development of various treatments for atrial fibrillation, the number of deaths due to their side effects has not decreased. Recently used treatments for atrial fibrillation are aimed not at controlling atrial fibrillation itself, but at reducing stroke, a side effect of atrial fibrillation. While numerous heart failure treatments have been developed, side effects such as worsening heart failure or death still occur in approximately 20% of patients, necessitating the development of new treatment methods.

[0005] Noninvasive procedures for treating atrial fibrillation are widely available and have shown remarkable efficacy. However, many patients experience recurrence of atrial fibrillation after these procedures. Therefore, the development of new treatments that can treat atrial fibrillation, prevent recurrence after atrial fibrillation procedures, or prevent the worsening of heart failure is urgent.

[0006] Meanwhile, a study analyzing differences in inflammation between patients with sinus rhythm and atrial fibrillation in heart tissue samples confirmed a significant correlation between caspase-1 expression and IL-1β expression and atrial fibrillation in patients with end-stage heart failure (Inflammasome activation in end-stage heart failure-associated atrial fibrillation, Szilvia Kugler et al., ESC Heart Failure 2022; 9: 2747-2752).

[0007] It is known that prointerleukin-1β, the inactive form of IL-1β, acts as a mediator that induces inflammation by being activated by caspase-1 (or ICE, interleukin-1 converting enzyme). Caspase is a cysteine ​​protease that exists in the form of a tetramer of α2β2, and caspase-1 to caspase-18 are known, which are involved in inflammation and apoptosis. In addition, Emricasan is known as a pan-caspase inhibitor that can inhibit various types of caspases.

[0008] Emricasan is a drug that suppresses inflammation and apoptosis, and inhibits caspase-1, which plays a key role in IL-1β activation, thereby suppressing major inflammatory responses. Emricasan is being developed and studied as a treatment for nonalcoholic steatohepatitis and cirrhosis, but its effects in treating or preventing heart disease are completely unknown.

[0009] There is a need to develop a treatment method with a new mechanism of action that can be considered as a treatment for patients with heart disease who do not respond to existing heart disease treatments or whose heart disease relapses despite repeated treatments.

[0010] The inventor of the present invention, as a result of efforts to develop a treatment for heart disease, discovered that a caspase inhibitor (e.g., emricasan) can suppress atrial fibrillation and heart failure in an animal model of atrial fibrillation and heart failure by suppressing apoptosis and inflammatory activity, thereby completing the present invention.

[0011] [1] In one aspect of the present invention, the present invention relates to a pharmaceutical composition for preventing or treating heart disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof.

[0012] [2] In the above [1], the caspase inhibitor may be a pan-caspase inhibitor or a selective caspase inhibitor.

[0013] [3] In the above [1] or [2], the caspase inhibitor may be Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-TERT-BUTYLPHENYLAMINO)-2-OXOACETAMIDO)PROPANAMIDO)-4-OXO-5-(2,3,5,6-TETRAFLUOROPHENOXY)PENTANOIC ACID):

[0014] [Chemical Formula I]

[0015]

[0016] [4] In any one of the above [1] to [3], the heart disease is atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), ventricular tachycardia, cardiac failure, myocardial infarction, cardiomyopathy, myocarditis, coronary artery disease, valvular heart disease, arrhythmia, pulmonary hypertension, congenital heart disease, hypertensive cardiomegaly, hypertrophic cardiomyopathy, hypertensive heart disease, and aortic valve It may be one or more selected from the group consisting of stenosis (Aortic valve stenosis).

[0017] [5] In the above [4], the heart disease may be atrial fibrillation, heart failure, or cardiac hypertrophy due to hypertension.

[0018] [6] In any one of [1] to [5] above, the pharmaceutical composition may be administered orally or parenterally.

[0019] [7] In the above [6], the pharmaceutical composition may be administered orally.

[0020] [8] In one aspect of the present invention, the present invention relates to a method for preventing or treating heart disease, comprising a step of administering to a subject a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof.

[0021] [9] In the above [8], the caspase inhibitor may be a pro-caspase inhibitor or a selective caspase inhibitor.

[0022]

[0010] In the above [8] or [9], the caspase inhibitor may be Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid).

[0023]

[0011] In any one of the above [8] to

[0010] , the heart disease may be at least one selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, ventricular tachycardia, heart failure, myocardial infarction, cardiomyopathy, myocarditis, coronary artery disease, valvular disease, arrhythmia, pulmonary hypertension, congenital heart disease, cardiac hypertrophy due to hypertension, hypertrophic cardiomyopathy, hypertensive heart disease, and aortic valve stenosis.

[0024]

[0012] In the above

[0011] , the heart disease may be atrial fibrillation, heart failure, or cardiac hypertrophy due to hypertension.

[0025]

[0013] In any one of the above [8] to

[0012] , the administration may be oral or parenteral administration.

[0026]

[0014] In the above

[0013] , the administration may be oral administration.

[0027]

[0015] In one aspect of the present invention, the present invention relates to the use of a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any of the above [1] to [7] for the manufacture of a medicament for preventing or treating heart disease.

[0028]

[0016] In one aspect of the present invention, the present invention relates to a use of a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of [1] to [7] for preventing or treating heart disease.

[0029]

[0017] In one aspect of the present invention, the present invention relates to a kit for preventing or treating heart disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of [1] to [7].

[0030] The caspase inhibitor and pharmaceutically acceptable salt thereof according to the present invention have excellent effects in inhibiting apoptosis and / or inflammatory activity, and exhibit effects in preventing or treating heart disease.

[0031] In addition, the caspase inhibitor of the present invention and its pharmaceutically acceptable salt can be administered orally, providing superior patient convenience compared to existing therapeutic agents.

[0032] Figure 1 illustrates a method for measuring atrial fibrillation susceptibility by observing the heartbeat of a mouse model of heart failure and atrial fibrillation exposed to angiotensin II for 4 weeks and artificially inducing atrial fibrillation using an electrode catheter in the heart.

[0033] Figure 2 shows the results of observing the heart rate (HR) by measuring the body surface electrocardiogram in the control group (vehicle QD 4-week oral administration group) and the emricasan administration group (emricasan 20 mg / kg 4-week oral administration group) of the heart failure and atrial fibrillation mouse model of Figure 1.

[0034] Figure 3 shows the frequency of spontaneous afib detection in the control group (vehicle QD 4-week oral administration group) and the emrica acid administration group (emrica acid 20 mg / kg 4-week oral administration group) of the heart failure and atrial fibrillation mouse model of Figure 1, as measured by electrocardiogram (ECG).

[0035] Figure 4 shows the success rate of induction (Afib inducibility) when artificial atrial fibrillation was attempted in the control group (4-week oral administration of vehicle QD group) and the emrica acid administration group (4-week oral administration of emrica acid 20 mg / kg group) of the heart failure and atrial fibrillation mouse model of Figure 1.

[0036] Figure 5 shows the intensity of electrical stimulation when artificial atrial fibrillation was successfully induced in the control group (4-week oral administration of vehicle QD group) and the emrica acid administration group (4-week oral administration of emrica acid 20 mg / kg group) of the heart failure and atrial fibrillation mouse model of Figure 1.

[0037] Figure 6 shows the ratio of heart weight to body weight (Heart weight / Body weight) in the control group (4-week oral administration of vehicle QD group) and the emricasan administration group (4-week oral administration of emricasan 20 mg / kg group) of the heart failure and atrial fibrillation mouse model of Figure 1.

[0038] Figure 7 shows the results of observing heartbeats (QRS interval, QT interval, QTc interval) using electrocardiogram (ECG) before inducing artificial atrial fibrillation by burst pacing in animal models (6 groups in total: WT+saline+vehicle, WT+AngII+vehicle, WT+AngII+Drug, KO+saline+vehicle, KO+AngII+vehicle, KO+AngII+Drug) in which heart failure and atrial fibrillation were induced using the method of Figure 1 in clonal hematopoietic mice (KO) and bone marrow transplantation negative control mice (WT).

[0039] Figure 8 shows the results of confirming the inducibility of arrhythmia in each group through an atrial pacing experiment using the jugular vein in the groups described in Figure 7.

[0040] Figure 9 shows the results of confirming fibrosis through Masson's trichrome staining in the atrial tissue of the group described in Figure 7.

[0041] Figure 10 shows the results of confirming the expression levels of biomarkers (MMP9, collagen I, collagen III) related to fibrosis in the atrial tissue of the group described in Figure 7 by western blot.

[0042] Figure 11 shows the results of confirming the expression levels of biomarkers related to inflammation (TNF-α, IL-1β, IL-6) in the atrial tissue of the group described in Figure 7 using western blot.

[0043] Figure 12 shows the results of confirming the expression levels of biomarkers (p-RYR2(ser2814) / total-RYR2, p-CaMKII / total-CaMKII, p-PLB / total-PLB) related to calcium handling in the atrial tissue of the group described in Figure 7 by western blot.

[0044] Hereinafter, the present invention will be described in more detail.

[0045] Meanwhile, each description and embodiment disclosed in the present invention can also be applied to each other description and embodiment. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions described below.

[0046] Furthermore, those skilled in the art will recognize or be able to ascertain, through routine experimentation, numerous equivalents to the specific embodiments of the invention described herein. Furthermore, such equivalents are intended to be encompassed by the present invention.

[0047]

[0048] definition

[0049] As used herein, the term "consisting of" means that the proportion of a particular component(s) totals 100%. The components or features following the term "consisting of" may be essential or mandatory.

[0050] As used herein, the term "comprising" means the presence of a feature, step, or component described below, but does not exclude the presence or addition of one or more features, steps, or components. Components or features described below "comprising" in this specification may be essential or mandatory, but some embodiments may further include other optional or non-essential components or features.

[0051] In this specification, the term "comprising" may, in some implementations, be modified to refer to "consisting essentially of" or "consisting of."

[0052] In this specification, the term "caspase" refers to a cysteine ​​protease that exists in the form of a tetramer of the α2β2 type, and is involved in inflammation and apoptosis. Meanwhile, various types of caspases are known, from caspase-1 to caspase-18, and initiator caspases and effector caspases exist as caspases involved in apoptosis. Caspase-1, caspase-4, caspase-5, and caspase-11 are known to be involved in inflammation, and caspase-2, caspase-8, caspase-9, and caspase-10 are known as initiator caspases, and caspase-3, caspase-6, and caspase-7 are known as effector caspases.

[0053] As used herein, the term "caspase inhibitor" refers to a compound that can control inflammation or apoptosis caused by the action of caspases by inhibiting their activity. Among caspase inhibitors, irreversible inhibitors are known to exhibit more effective inhibitory effects because they have a mechanism of inhibiting apoptosis by irreversibly inactivating the enzyme.

[0054] As used herein, the term "salt" refers to a salt that retains the biological effects and properties of the parent compound and is not biologically harmful at the administered dose, and includes "pharmaceutically acceptable salts."

[0055] As used herein, the term "pharmaceutically acceptable salt" means a salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reactions, or similar problems within the scope of sound medical judgment, and that has a reasonable benefit / risk ratio, and may refer to non-toxic acid addition salts derived from inorganic and organic acids. For example, pharmaceutically acceptable salts are described in detail in SMBerge et al. J. Pharmaceutical Sciences, 1977, 66:1 et seq.

[0056] In this specification, the term "prevention" means any act of suppressing the onset of clinical symptoms of a disease or suppressing heart failure or atrial fibrillation by administering a pharmaceutical composition according to the present invention.

[0057] In this specification, the term “treatment” means any action by which the clinical symptoms of a disease are improved or beneficially changed by administration of the pharmaceutical composition according to the present invention.

[0058] As used herein, the term "improvement" refers to an observable beneficial effect of a treatment. A beneficial effect may be evidenced by a delayed onset of clinical symptoms of a disease in a subject, a reduction in the severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the subject's overall health or well-being, or other variables well-known in the art to be specific to a particular disease.

[0059] As used herein, the term "compound" is intended to include pharmaceutically acceptable salts of the compounds of the present invention, even if no pharmaceutically acceptable salt thereof is mentioned. The compounds and salts may form solvates or exist in substantially uncomplexed forms, for example, in anhydrous form. The solvate refers to a molecular complex in which solvent molecules, for example, a crystallization solvent, are incorporated into the crystal lattice. When the solvent incorporated into the solvate is water, the molecular complex is referred to as a hydrate. Pharmaceutically acceptable solvates include hydrates, methanolates and ethanolates, acetonitrileates, and the like. These compounds may also exist in polymorphic forms.

[0060] In this specification, the term "cardiovascular disease (CVD)" is a general term for diseases occurring in the heart, and may be at least one selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, ventricular tachycardia, heart failure, myocardial infarction, cardiomyopathy, myocarditis, coronary artery disease, valvular disease, arrhythmia, pulmonary hypertension, congenital heart disease, cardiac hypertrophy due to hypertension, hypertrophic cardiomyopathy, hypertensive heart disease, and aortic valve stenosis, but is not limited thereto.

[0061] As used herein, the term "atrial fibrillation" refers to a type of arrhythmia in which the atria, the upper chambers of the heart, beat irregularly and rapidly. This refers to a condition in which the atria fail to contract properly and contract irregularly. Irregular electrical signals generated in various parts of the atria prevent the atria from contracting properly, preventing blood from the atria from properly flowing to the ventricles, leading to irregular heartbeats and an increased risk of blood clots.

[0062] As used herein, the term "heart failure" refers to a disease caused by a structural or functional abnormality in the heart, which reduces the heart's ability to diastolic or contractile function, resulting in an inability to adequately supply blood to body tissues. A key symptom of heart failure is cardiac hypertrophy, which is typically discovered before heart failure.

[0063] As used herein, the term "hypertensive cardiac hypertrophy" refers to the thickening of the walls of the heart muscle, particularly the left ventricle, due to chronic high blood pressure. Hypertension causes the heart to work harder to pump blood, which gradually thickens the heart muscle and can lead to complications such as decreased heart function, arrhythmia, and heart failure over time.

[0064] As used herein, the term "therapeutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined based on factors including the subject's body weight, sex, age, health status, severity, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field.

[0065] As used herein, the term "kit" refers to a packaged product comprising components for administering the caspase inhibitor of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same for the treatment of heart disease. The kit preferably includes a container or box for holding the components of the kit. The box or container may be accompanied by a protocol or label approved by a pharmaceutical regulatory authority. The components of the present invention are contained within a box or container made of plastic, polyethylene, polypropylene, ethylene, or propylene. The container may be a tube or bottle with a cap. The kit may also include instructions for administering the caspase inhibitor of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

[0066]

[0067] Pharmaceutical composition for preventing or treating heart disease

[0068] The present invention provides a pharmaceutical composition for preventing or treating heart disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof.

[0069] The above caspase inhibitor refers to a substance (e.g., a compound, an antibody, etc.) that can control inflammation or apoptosis caused by the action of caspase by inhibiting the activity of caspase.

[0070] In one embodiment of the present invention, the caspase inhibitor may be a pro-caspase inhibitor or a selective caspase inhibitor capable of selectively inhibiting the activity of a specific caspase. The pro-caspase inhibitor is a substance capable of inhibiting the activity of two or more caspases, and may be at least one selected from the group consisting of GS-9540 (nivocasan), Q-VD-OPh (Quinoline-Val-Asp-OPh) / Q-VD(OMe)-OPh, VX-166, and emricasan, but is not limited thereto. The emricasan may be referred to as IDN-6556, CS-1040, or PF-03491390. In addition, the pro-caspase inhibitor may be a substance that inhibits caspase-1.

[0071] In one aspect of the present invention, a pharmaceutical composition for preventing or treating heart disease comprising the pro-caspase inhibitor is provided.

[0072] In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating atrial fibrillation comprising the procaspase inhibitor.

[0073] In addition, the present invention provides a pharmaceutical composition for preventing or treating heart failure comprising the pro-caspase inhibitor.

[0074] In addition, the present invention provides a pharmaceutical composition for preventing or treating cardiac hypertrophy due to hypertension, comprising the above-described pro-caspase inhibitor.

[0075] 본 발명의 일 구현예에서, 상기 선택적 캐스파제 저해제는 VE-16084((3R)-5-(2,6-dichlorobenzoyl)oxy-3-[[(2S)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-4-oxopentanoic acid), SDZ-224-015([(3S)-3-[[(2S)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-2-oxo-3-(2-oxoethoxy)propyl] 2,6-dichlorobenzoate), AS101([(5Z)-5-(2,6-dioxo-1,3-dipropylpurin-8-ylidene)-1-methyl-2H-pyrazol-3-yl] 2-[(3,4-dimethoxyphenyl)amino]acetate), M826(3-[2-[5-Tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methylamino]-2-oxopyrazin-1-yl]butanoylamino]-5-(hexyl-methylamino)-4-oxopentanoic acid), Ac-YVAD-CHO(Acetyl-Tyr-Val-Ala-Asp-Aldehyde), Ac-YVAD-CMK(Acetyl-Tyr-Val-Ala-Asp-Chloromethyl ketone), CIB-1476, Minocycline, NSC697923, Pralnacasan, Uracil 20, VRT-043198 (the active metabolite of VX-765), VX-740 (pralnacasan), VX-765 (belnacasan), YVAD(Tyr-Val-Ala-Asp), Z-VAD-CHO(Benzyloxycarbonyl-Val-Ala-Asp-Aldehyde), Z-VAD-FMK(Benzyloxycarbonyl-Val-Ala-Asp-Fluoromethyl Ketone),It may be at least one selected from the group consisting of Z-WEHD-FMK (Benzyloxycarbonyl-Trp-Glu-His-Asp-Fluoromethyl Ketone), Z-YVAD-CHO (Benzyloxycarbonyl-Tyr-Val-Ala-Asp-Aldehyde), Z-YVAD-FMK (Benzyloxycarbonyl-Tyr-Val-Ala-Asp-Fluoromethyl Ketone) and Ac-DEVD-CHO (Acetyl-Asp-Glu-Val-Asp-Aldehyde), but is not limited thereto. The selective caspase inhibitor may include a substance capable of inhibiting caspase-1 among the above-mentioned pro-caspase inhibitors (for example, emricasan (CS-1040, IDN-6556, PF-03491390)).

[0076] In another embodiment of the present invention, the pro-caspase inhibitor may be a substance capable of inhibiting a caspase effector. In addition, the pro-caspase inhibitor may be a substance capable of inhibiting at least one of caspase-1, caspase-3, and caspase-8, or the pro-caspase inhibitor may be a substance capable of inhibiting caspase-1. Preferably, the pro-caspase inhibitor is a substance that essentially inhibits the activity of caspase-1, including, but not limited to, emricasan.

[0077] In one embodiment of the present invention, the caspase inhibitor may be Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid).

[0078] [Chemical Formula I]

[0079]

[0080] In one embodiment of the present invention, a pharmaceutically acceptable salt of the caspase inhibitor may be prepared from an inorganic acid, an organic acid, or a base. The compound of the present invention may be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid, an organic acid, or a base.

[0081] In another embodiment of the present invention, the pharmaceutically acceptable salt of the caspase inhibitor is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid (tosylate salt), 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, acetic acid, trifluoroacetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, alkali cations (e.g., Li + , Na + or K + ), alkaline earth cations (e.g., Mg 2+ , Ca 2+ or Ba 2+ ), an ammonium cation, an organic base containing an aliphatic and aromatic substituted ammonium, triethylamine, N,N-diethylamine, N,N-dicyclohexylamine, lysine, pyridine, N,N-dimethylaminopyridine (DMAP), 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene (DBN) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU).

[0082] The pharmaceutical composition of the present invention can be formulated and used in the form of tablets, pills, powders, granules, capsules, suspensions, liquids, emulsions, syrups, or injection solutions according to conventional methods.

[0083] In addition, the pharmaceutical composition of the present invention may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc. as a carrier, excipient, or diluent. In addition, when formulating the pharmaceutical composition of the present invention, it may include a diluent or excipient such as a filler, a bulking agent, a binder, a wetting agent, a disintegrating agent, or a surfactant.

[0084] In one embodiment of the present invention, the heart disease may be at least one selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, ventricular tachycardia, heart failure, myocardial infarction, cardiomyopathy, myocarditis, coronary artery disease, valvular disease, arrhythmia, pulmonary hypertension, congenital heart disease, cardiac hypertrophy due to hypertension, hypertrophic cardiomyopathy, hypertensive heart disease, and aortic valve stenosis.

[0085] Specifically, the heart disease may be atrial fibrillation, heart failure, or cardiac hypertrophy due to hypertension.

[0086] In one embodiment of the present invention, the pharmaceutical composition may be administered orally or parenterally.

[0087] In one embodiment of the present invention, the pharmaceutical composition may be administered orally. Parenteral administration may be administered by topical application to the skin or by intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[0088] Solid preparations for oral administration may include tablets, pills, powders, granules, or capsules, and these solid preparations may include at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to the excipients, they may also include lubricants such as magnesium stearate or talc. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, or syrups, and may include various excipients, such as wetting agents, sweeteners, flavoring agents, or preservatives, in addition to water or liquid paraffin.

[0089] Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, or suppositories. Non-aqueous solutions and suspensions may include, for example, vegetable oils such as propylene glycol, polyethylene glycol, or olive oil, and injectable esters such as ethyl oleate.

[0090] In one embodiment of the present invention, the pharmaceutical composition may be administered in a pharmaceutically effective amount.

[0091] Furthermore, the pharmaceutical composition of the present invention can be administered as a single agent or in combination with other agents, sequentially or simultaneously with conventional agents, or in single or multiple doses. Taking all of the above factors into consideration, it is important to administer an amount that achieves maximum effect with the minimum amount possible without causing side effects, and this can be appropriately determined by those skilled in the art.

[0092] The composition according to the present invention may further comprise a surfactant. Surfactants include, but are not limited to, lipids such as phospholipids, phosphatidylcholine, lecithin, cardiolipin, fatty acids, phosphatidylethanolamine, phosphatides, tyloxapol, polyethylene glycol, PEG 400, PEG 1500, PEG 2000, poloxamer 407, poloxamer 188, polysorbate 80, polysorbate 20, sorbitan lithium, sorbitan stearate, sorbitan palmitate, or mixtures thereof.

[0093] The pharmaceutical composition of the present invention may further comprise a stabilizer or gelling agent. Such stabilizers or gelling agents include, but are not limited to, propylene glycol monopalmitostearate, glyceryl monostearate, glyceryl dibehenate, glyceryl distearate, hydrogenated fats, polyvinylpyrrolidone, polyethylene, glycerol, polyoxyethylene stearate, sorbitan fatty acid esters, cholesterol, macrogol-20-glycerol monostearate, poloxamer 124, isopropyl myristate, isopropyl palmitate, colloidal silica, hydrophobic colloidal silica, magnesium stearate, zinc stearate, aluminum stearate, lanolin alcohol, organoclay, petrolatum, or polyoxyl 6 stearate.

[0094] The composition according to the present invention may further comprise a polymer-based carrier. The polymer-based carrier includes, but is not limited to, for example, cellulose, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), carboxymethyl cellulose (CMC), methylcellulose (MC), hydroxyethylcellulose (HEC), amylase, amylopectin, dextran, polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), polyacrylic acid derivatives such as HEMA, acrylic polymers such as polymethacrylic acid derivatives, carbopol, derivatives thereof, or mixtures thereof.

[0095] The pharmaceutical composition according to the present invention may further comprise an organic cosolvent. Organic cosolvents include, but are not limited to, ethylene glycol, propylene glycol, N-methyl pyrrolidone, 2-pyrrolidone, 3-pyrrolidinol, 1,4-butanediol, dimethylglycol monomethyl ether, diethylene glycol monomethyl ether, solketal, glycerol, polyethylene glycol, or polypropylene glycol.

[0096] The pharmaceutical composition according to the present invention may additionally comprise a pH-active ingredient. Suitable pH-active ingredients, such as buffers or pH-adjusting agents, include, but are not limited to, disodium phosphate, monosodium phosphate, boric acid, sodium borate, sodium citrate, hydrochloric acid, or sodium hydroxide.

[0097] The pharmaceutical composition according to the present invention may additionally comprise an osmotically active ingredient. The osmotically active ingredient includes, but is not limited to, sodium chloride, mannitol, or glycerol.

[0098] The concentration and frequency of administration of the active ingredient used in the present invention may vary depending on, for example, the compound used, the type of subject (e.g., animal or human), age, body weight, symptoms, desired therapeutic effect, administration method, dosage, or treatment period. Accordingly, an appropriate concentration and frequency of administration may be selected as needed.

[0099] The pharmaceutical composition of the present invention may comprise a single active ingredient or a combination of two or more active ingredients. In combinations of multiple active ingredients, the respective contents may be appropriately increased or decreased, taking into account their therapeutic efficacy and safety.

[0100] The pharmaceutical composition according to the present invention may further comprise a preservative. Preservatives include, but are not limited to, benzalkonium chloride, alkyldimethylbenzylammonium chloride, cetrimide, cetylpyridinium chloride, benzododecinium bromide, benzethonium chloride, thiomersal, chlorobutanol, benzyl alcohol, phenoxethanol, phenylethyl alcohol, sorbic acid, methyl, propyl paraben, chlorhexidine digluconate, EDTA, or mixtures thereof.

[0101] Additionally, the composition of the present invention may include a sustained-release form, such as, but not limited to, a gel formulation, a liposome formulation, a lipid microemulsion formulation, a microsphere formulation, a nanosphere formulation, or an implant formulation, to provide a sustained release of the active compound.

[0102]

[0103] How to prevent or treat heart disease

[0104] The present invention provides a method for preventing or treating heart disease, comprising administering to a subject a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof.

[0105] The above caspase inhibitor refers to a substance (e.g., a compound, an antibody, etc.) that can control inflammation or apoptosis caused by the action of caspase by inhibiting the activity of caspase.

[0106] In one embodiment of the present invention, the caspase inhibitor may be a pro-caspase inhibitor or a selective caspase inhibitor capable of selectively inhibiting the activity of a specific caspase. The pro-caspase inhibitor is a substance capable of inhibiting the activity of two or more caspases, and may be at least one selected from the group consisting of GS-9540 (nivocasan), Q-VD-OPh (Quinoline-Val-Asp-OPh) / Q-VD (OMe)-OPh, VX-166, and emricasan, but is not limited thereto. The emricasan may be referred to as IDN-6556, CS-1040, or PF-03491390. In addition, the pro-caspase inhibitor may be a substance that inhibits caspase-1.

[0107] The present invention provides a method for preventing or treating heart disease, comprising a step of administering to a subject a therapeutically effective amount of the pro-caspase inhibitor or a pharmaceutically acceptable salt thereof.

[0108] The present invention provides a method for preventing or treating atrial fibrillation, comprising administering to a subject a therapeutically effective amount of the procaspase inhibitor or a pharmaceutically acceptable salt thereof.

[0109] The present invention provides a method for preventing or treating heart failure, comprising administering to a subject a therapeutically effective amount of the procaspase inhibitor or a pharmaceutically acceptable salt thereof.

[0110] The present invention provides a method for preventing or treating cardiac hypertrophy due to hypertension, comprising administering to a subject a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof.

[0111] 본 발명의 일 구현예에서, 상기 선택적 캐스파제 저해제는 VE-16084((3R)-5-(2,6-dichlorobenzoyl)oxy-3-[[(2S)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-4-oxopentanoic acid), SDZ-224-015([(3S)-3-[[(2S)-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-2-oxo-3-(2-oxoethoxy)propyl] 2,6-dichlorobenzoate), AS101([(5Z)-5-(2,6-dioxo-1,3-dipropylpurin-8-ylidene)-1-methyl-2H-pyrazol-3-yl] 2-[(3,4-dimethoxyphenyl)amino]acetate), M826(3-[2-[5-Tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methylamino]-2-oxopyrazin-1-yl]butanoylamino]-5-(hexyl-methylamino)-4-oxopentanoic acid), Ac-YVAD-CHO(Acetyl-Tyr-Val-Ala-Asp-Aldehyde), Ac-YVAD-CMK(Acetyl-Tyr-Val-Ala-Asp-Chloromethyl ketone), CIB-1476, Minocycline, NSC697923, Pralnacasan, Uracil 20, VRT-043198(the active metabolite of VX-765), VX-740(pralnacasan), VX-765(belnacasan), YVAD(Tyr-Val-Ala-Asp), Z-VAD-CHO(Benzyloxycarbonyl-Val-Ala-Asp-Aldehyde), Z-VAD-FMK(Benzyloxycarbonyl-Val-Ala-Asp-Fluoromethyl Ketone),It may be at least one selected from the group consisting of Z-WEHD-FMK (Benzyloxycarbonyl-Trp-Glu-His-Asp-Fluoromethyl Ketone), Z-YVAD-CHO (Benzyloxycarbonyl-Tyr-Val-Ala-Asp-Aldehyde), Z-YVAD-FMK (Benzyloxycarbonyl-Tyr-Val-Ala-Asp-Fluoromethyl Ketone) and Ac-DEVD-CHO (Acetyl-Asp-Glu-Val-Asp-Aldehyde), but is not limited thereto. The selective caspase inhibitor may include a substance capable of inhibiting caspase-1 among the above-mentioned pro-caspase inhibitors (for example, emricasan (CS-1040, IDN-6556, PF-03491390)).

[0112] In another embodiment of the present invention, the pro-caspase inhibitor may be a substance capable of inhibiting a caspase effector. In addition, the pro-caspase inhibitor may be a substance capable of inhibiting at least one of caspase-1, caspase-3, and caspase-8, or the pro-caspase inhibitor may be a substance capable of inhibiting caspase-1. Preferably, the pro-caspase inhibitor is a substance that essentially inhibits the activity of caspase-1, including, but not limited to, emricasan.

[0113] In one embodiment of the present invention, the caspase inhibitor may be Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid).

[0114] [Chemical Formula I]

[0115]

[0116] In one embodiment of the present invention, the heart disease may be at least one selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, ventricular tachycardia, heart failure, myocardial infarction, cardiomyopathy, myocarditis, coronary artery disease, valvular disease, arrhythmia, pulmonary hypertension, congenital heart disease, cardiac hypertrophy due to hypertension, hypertrophic cardiomyopathy, hypertensive heart disease, and aortic valve stenosis.

[0117] Specifically, the heart disease may be atrial fibrillation, heart failure, or cardiac hypertrophy due to hypertension.

[0118] In one embodiment of the present invention, the pharmaceutical composition may be administered orally or parenterally.

[0119] In one embodiment of the present invention, the pharmaceutical composition may be administered orally. Parenteral administration may be administered by topical application to the skin or by intraperitoneal injection, intrarectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

[0120] In one embodiment of the present invention, the administration may be oral administration.

[0121] In one embodiment of the present invention, the dosage of a caspase inhibitor (e.g., Emricasan) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, administered to a mammal, particularly a human, according to the present invention should be sufficient to produce the desired response. Such response includes prevention or reversal of adverse effects of a disease for which treatment is desired or for which a desired benefit is obtained. Those skilled in the art will recognize that the dosage will depend on various factors, such as age, condition, weight of the subject, the specific type or extent of the disease. The size of the dosage may be determined by the route, timing, and frequency of administration, the combination of specific compounds administered, and the presence, nature, or extent of any adverse effects that may accompany the desired physiological effect. Those skilled in the art will also recognize that various conditions or disease states may require prolonged treatment, including multiple administrations.

[0122] The appropriate dosage and administration method of the present invention can be determined using conventional techniques known to those skilled in the art. Generally, treatment may be initiated at a dose lower than the optimal dose of the compound. The dosage may then be increased in small increments until the optimal effect is achieved under the appropriate circumstances.

[0123] In one embodiment of the present invention, the preventive or therapeutic method may typically comprise administering from about 0.1 to about 300 mg of one or more of the compounds per kilogram of body weight of the animal or mammalian subject. The therapeutically effective amount of the administered compound may vary depending on the desired effect and the factors set forth above.

[0124] The dosage of the present invention can be calculated based on body surface area. Therapeutically effective dosages can be administered over an extended period of time or as multiple daily doses. Accordingly, the dosage can be calculated using the subject's body surface area, based on the appropriate range and preferred dosing schedule cited above.

[0125] The term "subject" as used herein may be a mammal. Mammals according to the present invention include, but are not limited to, humans, canines, felines, bovines, caprines, equines, ovines, porcines, rodents, lagomorphs, primates, or in utero mammals. The subject may be of either sex and at any stage of development. The subject may alternatively be referred to as a "subject."

[0126] In one embodiment of the present invention, the subject may be a human. The subject may also be a human suspected of having a heart disease, such as atrial fibrillation, heart failure, or cardiac hypertrophy due to hypertension.

[0127]

[0128] For the prevention or treatment of heart disease

[0129] In one aspect of the present invention, the present invention provides a use of a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for preventing or treating heart disease.

[0130] In another aspect of the present invention, the present invention provides the use of a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same for the manufacture of a medicament for preventing or treating heart disease.

[0131] Among the terms or elements mentioned in the above use, the composition of the pharmaceutical composition and the preventive or therapeutic method are understood to be the same as those mentioned in the description of the pharmaceutical composition and the preventive or therapeutic method above.

[0132]

[0133] Kit

[0134] The present invention provides a kit for preventing or treating heart disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.

[0135] Among the terms or elements mentioned in the above kit, the composition of the caspase inhibitor or a pharmaceutically acceptable salt thereof or pharmaceutical composition is understood to be the same as mentioned in the description of the above pharmaceutical composition.

[0136] In one embodiment of the present invention, the kit may further include a user manual describing optimal reaction conditions. The manual may include a pamphlet, leaflet-style guidebook, a label attached to the kit, or a description on the surface of the package containing the kit. Furthermore, the manual may include information disclosed or provided through electronic media, such as the Internet.

[0137] Hereinafter, to aid understanding of the present invention, examples will be given in detail. However, the following examples are intended only to illustrate the content of the present invention and are not intended to limit the scope of the present invention to the following examples.

[0138]

[0139] Example

[0140] Example 1. Establishment of an animal model of heart failure and atrial fibrillation induced by hypertension induced by prolonged exposure to angiotensin II.

[0141] Long-term injection of excessive amounts of angiotensin II into mice can increase blood pressure and induce heart failure and atrial fibrillation accompanied by cardiac hypertrophy and cardiac structural changes, and thus are widely used as a model for heart failure and atrial fibrillation (European Heart Journal, Volume 42, Issue 43, 14 November 2021, Pages 4420-4430). Therefore, in order to confirm the cardiac disease treatment effect of the caspase inhibitor of the present invention, an osmotic pump of an appropriate capacity was selected, and angiotensin II dilution calculated considering the weight of the animal was filled, and 2000 mg / kg / day of angiotensin II was continuously infused for 28 days to induce heart failure and atrial fibrillation.

[0142] At this time, the weight of the pump without diluent, the weight of the pump with diluent, and the weight of the pump after removal from the animal 28 days were recorded to allow calculation of the amount of angiotensin II injected during the experimental period.

[0143] Osmotic pumps containing diluted solutions were prepared according to the manufacturer's instructions (ALZET® MODEL 2004) and implanted subcutaneously on the dorsal side of mice, after which the incision site was fixed. The experimental group was administered 20 mg / kg of emricasan, and the control group was administered the same volume of vehicle once daily by oral gavage for 28 days.

[0144]

[0145] Example 2. Preventive and therapeutic effects of heart failure and atrial fibrillation in animal models of heart failure and atrial fibrillation.

[0146] Animal models that had been administered angiotensin II and oral drugs for 28 days were anesthetized with 2% isoflurane, and heart rate and body surface electrocardiogram lead II were recorded using a subdermal needle electrode (Fig. 1).

[0147] Afterwards, a 1.1 French octapolar electrophysiology catheter was inserted into the heart through the right jugular vein, and electrical stimulation was applied to the right atrium using the burst pacing method, and then it was observed whether atrial fibrillation was induced.

[0148] The burst pacing method is a method of confirming whether atrial fibrillation is observed on the electrocardiogram by applying increasingly stronger electrical stimulation at regular intervals while reducing the basic cycle length (BCL) from 40 ms to 20 ms in 2 ms intervals.

[0149] Electrical stimulation of the heart is administered continuously for 5 seconds at a specified basic cycle length, then stopped. Atrial fibrillation is observed on the electrocardiogram within 30 seconds. If it persists for more than 1 second, it is determined to have been induced. Atrial fibrillation is determined by having an irregular RR interval without a recognizable P wave on the electrocardiogram.

[0150] Additionally, to observe the degree of cardiac hypertrophy, the hearts of mice were obtained, their weights were measured, and the heart weight to body weight ratio was measured.

[0151]

[0152] Example 3. Preventive and therapeutic effects of procaspase inhibitors on heart failure and atrial fibrillation.

[0153] Before artificially inducing atrial fibrillation using burst pacing, surface electrocardiography (SEC) was measured to monitor heart rate and spontaneous atrial fibrillation. The group administered emricasan showed a reduced increase in heart rate induced by angiotensin II compared to the control group (Figure 2).

[0154] In addition, in the control group, spontaneous atrial fibrillation was observed in all animals without artificial atrial fibrillation induction, but in the group administered with emricasan, it was observed in only one animal out of five, confirming a significant difference (Fig. 3).

[0155] Furthermore, the control group showed a lower susceptibility to atrial fibrillation, with burst pacing inducing artificial atrial fibrillation in all animals, whereas the group administered emricasan showed a lower susceptibility to atrial fibrillation, with burst pacing inducing artificial atrial fibrillation in only two out of five animals (Fig. 4).

[0156] In the control group, atrial fibrillation was induced at a fundamental cycle length of 33.5 ms on average in burst pacing. However, in the group administered emricasan, atrial fibrillation was induced at a fundamental cycle length of 25 ms on average in only two animals, indicating that a stronger stimulus was required to induce atrial fibrillation compared to the control group (Fig. 5). Here, in individuals in which atrial fibrillation was not induced even at a fundamental cycle length of 20 ms, statistical analysis was performed assuming that atrial fibrillation was induced at 20 ms.

[0157] Meanwhile, in order to observe the degree of cardiac hypertrophy, the hearts of mice were obtained, their weights were measured, and the heart weight to body weight ratio was measured. As a result, the heart weight to body weight ratio was reduced in the group administered with emricasan compared to the control group (Fig. 6).

[0158] Considering that cardiac hypertrophy is a major symptom of heart failure, it was confirmed from the above results that administration of the pharmaceutical composition of the present invention is effective in preventing or treating heart failure.

[0159]

[0160] Example 4. Preventive and therapeutic effects of a procaspase inhibitor on heart failure and atrial fibrillation in an animal model of chronic inflammation.

[0161] The phenomenon of proliferation of immune cells with mutations is called clonal hematopoiesis, and it is well known that it causes chronic inflammation and is related to the development of heart disease, especially atrial fibrillation or heart failure (Eur Heart J.2024 Mar 7;45(10):778-790.doi: 10.1093 / eurheartj / ehad869; Circulation. Volume 148, Number 15.https: / doi.org / 10.1161 / CIRCULATIONAHA.123.064170).

[0162] Therefore, in order to confirm the therapeutic effect of the caspase inhibitor of the present invention on heart failure and atrial fibrillation through chronic inflammation suppression, a clonal hematopoietic animal model was prepared, and 24 clonal hematopoietic animals and 24 bone marrow transplantation negative control animals were supplied by Woojung Bio Co., Ltd.

[0163] The specific process for producing clonal hematopoietic animals and bone marrow transplantation-negative control animals supplied by Woojung Bio Co., Ltd. is as follows. Clonal hematopoiesis-induced group mice (KO) were produced by transplanting bone marrow containing 10% bone marrow cells from Tet2 gene-deficient mice (produced by KAIST (Korea Advanced Institute of Science and Technology)) into 8-week-old male mice (C57BL / 6J, supplied by Jackson lab Japan) whose bone marrow cells were killed by radiation. In addition, bone marrow transplantation-negative control animals (WT) were produced by transplanting bone marrow containing 10% bone marrow cells from mice with intact Tet2 genes into 8-week-old male mice (C57BL / 6J, supplied by Jackson lab Japan) whose bone marrow cells were killed by radiation. Twenty weeks after bone marrow transplantation, the animals were divided into three groups, which are listed in Table 1.

[0164] Test group Bone marrow transplantation Negative control group (WT) Clonal hematopoiesis induction group (KO) Saline infusion + vehicle administration (PO) 4 animals 4 animals Ang II infusion + vehicle administration (PO) 10 animals 10 animals Ang II infusion + Emricasan 20 mpk administration (PO) 10 animals 10 animals

[0165] For the three groups of animals, angiotensin II was administered and oral drugs were administered for 28 days in the same manner as in Example 2 to prepare an animal model for the development of heart failure and atrial fibrillation.

[0166] When observing the heartbeat using Surface ECG before inducing artificial atrial fibrillation with burst pacing, it was observed that the QRS interval and QT interval increased by angiotensin II administration in bone marrow transplantation negative control animals (WT) (p=0.08), but in the emricasan administration group, the increase in QRS interval and QT interval by angiotensin II administration was suppressed (p=0.04) (Fig. 7).

[0167]

[0168] In an atrial pacing experiment using the jugular vein, the inducibility of arrhythmia was confirmed for each group.

[0169] In both the bone marrow transplantation negative control (WT) and clonal hematopoiesis-induced (KO) groups, no arrhythmias were induced in the Saline-Vehicle group. Angiotensin II administration induced arrhythmias in 6 of 9 mice (67%) in the bone marrow transplantation negative control group and 5 of 9 mice (56%) in the clonal hematopoiesis-induced group. In contrast, emricasan-treated group suppressed the arrhythmogenic effect of angiotensin II administration in 3 of 10 mice (30%) in the bone marrow transplantation negative control group and 2 of 9 mice (22%) in the clonal hematopoiesis-induced group (Fig. 8, top).

[0170] Furthermore, when comparing the induction cycle length results, arrhythmia was induced in the emricasan-administered group with a stronger stimulus (shorter cycle length) (Figure 8, bottom right). These results confirmed that emricasan could effectively suppress arrhythmia induction by atrial pacing.

[0171]

[0172] Furthermore, Masson's trichrome staining was performed to confirm fibrosis in mouse atrial tissue.

[0173] The experimental results showed that angiotensin II administration increased fibrosis (p < 0.05) in both the bone marrow transplantation-negative control group (WT) and the clonal hematopoiesis-induced group (KO). On the other hand, when emricasan was administered, the fibrosis-increasing effect caused by angiotensin II administration was suppressed (Fig. 9). Even without angiotensin II administration, the clonal hematopoiesis-induced group (KO) showed higher fibrotic lesions than the bone marrow transplantation-negative control group (WT), indicating that clonal hematopoiesis can affect fibrosis.

[0174]

[0175] The expression levels of biomarkers associated with fibrosis in mouse atrial tissue were confirmed by western blot.

[0176] As a result of the analysis of MMP9, collagen I, and collagen III biomarkers, it was confirmed that the amount of fibrosis biomarkers increased by angiotensin II administration in both the bone marrow transplantation negative control group (WT) and the clonal hematopoiesis-induced group (KO), but when emricasan was administered, the increase in these fibrosis biomarkers was suppressed (Fig. 10).

[0177]

[0178] The expression levels of biomarkers related to inflammation in mouse atrial tissue were confirmed by western blot.

[0179] As a result of the analysis of TNF-α, IL-1β, and IL-6 biomarkers, it was confirmed that the amount of inflammatory biomarkers increased by angiotensin II administration in both the bone marrow transplantation negative control group (WT) and the clonal hematopoiesis-induced group (KO), but when emricasan was administered, the increase in inflammatory biomarkers was suppressed (Fig. 11).

[0180]

[0181] The expression levels of biomarkers related to calcium handling in mouse atrial tissue were confirmed by western blot.

[0182] As a result of p-RYR2(ser2814) / total-RYR2, p-CaMKII / total-CaMKII, and p-PLB / total-PLB biomarker analysis, the amount of calcium handling biomarkers increased by angiotensin II administration in both the bone marrow transplantation negative control group (WT) and the clonal hematopoiesis-induced group (KO), but when emricasan was administered, the increase in calcium handling biomarkers was suppressed (Fig. 12).

[0183] Taken together, these results suggest that emricasan can inhibit the occurrence of arrhythmias, increased QRS interval, increased QT interval, increased fibrotic lesions, and increased fibrosis biomarkers, inflammatory biomarkers, and calcium handling biomarkers induced by angiotensin II administration. These are all important biomarkers of atrial fibrillation, and emricasan showed an effect that can inhibit the occurrence of atrial fibrillation. Increased QRS interval and QT interval are associated with a poor prognosis of heart failure, and fibrosis of cardiac tissue is one of the important pathogenesis of heart failure, so emricasan showed an effect that can inhibit the occurrence of heart failure.

Claims

1. A pharmaceutical composition for preventing or treating heart disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition for preventing or treating heart disease, wherein the caspase inhibitor in paragraph 1 is a pan-caspase inhibitor or a selective caspase inhibitor.

3. A pharmaceutical composition for preventing or treating heart disease, wherein the caspase inhibitor is Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid) in the first or second paragraph: [Chemical Formula I] 4. In any one of paragraphs 1 to 3, the heart disease is atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia (PSVT), ventricular tachycardia, cardiac failure, myocardial infarction, cardiomyopathy, myocarditis, coronary artery disease, valvular heart disease, arrhythmia, pulmonary hypertension, congenital heart disease, hypertensive cardiomegaly, hypertrophic cardiomyopathy, hypertensive heart disease, and aortic valve. A pharmaceutical composition for preventing or treating heart disease, wherein the composition comprises at least one selected from the group consisting of aortic valve stenosis.

5. A pharmaceutical composition for preventing or treating heart disease, wherein the heart disease is atrial fibrillation, heart failure, or cardiac hypertrophy due to hypertension, in the fourth paragraph.

6. A pharmaceutical composition for preventing or treating heart disease, according to any one of claims 1 to 5, wherein the pharmaceutical composition is administered orally or parenterally.

7. A pharmaceutical composition for preventing or treating heart disease, wherein the pharmaceutical composition is administered orally in paragraph 6.

8. A method for preventing or treating heart disease, comprising administering to a subject a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof.

9. A method for preventing or treating heart disease in claim 8, wherein the caspase inhibitor is a pro-caspase inhibitor or a selective caspase inhibitor.

10. Method for preventing or treating heart disease according to claim 8 or 9, wherein the caspase inhibitor is Emricasan represented by the chemical formula I ((S)-3-((S)-2-(2-(2-tert-butylphenylamino)-2-oxoacetamido)propanamido)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid): [Chemical Formula I] 11. A method for preventing or treating heart disease according to any one of claims 8 to 10, wherein the heart disease is at least one selected from the group consisting of atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, ventricular tachycardia, heart failure, myocardial infarction, cardiomyopathy, myocarditis, coronary artery disease, valvular disease, arrhythmia, pulmonary hypertension, congenital heart disease, cardiac hypertrophy due to hypertension, hypertrophic cardiomyopathy, hypertensive heart disease, and aortic valve stenosis.

12. A method for preventing or treating heart disease in claim 11, wherein the heart disease is atrial fibrillation, heart failure, or cardiac hypertrophy due to hypertension.

13. A method for preventing or treating heart disease according to any one of claims 8 to 12, wherein the administration is oral or parenteral administration.

14. A method for preventing or treating heart disease, wherein the administration is oral administration in the 13th paragraph.

15. Use of a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claims 1 to 7 for the manufacture of a medicament for preventing or treating heart disease.

16. Use of a therapeutically effective amount of a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claims 1 to 7 for preventing or treating heart disease.

17. A kit for preventing or treating heart disease, comprising a caspase inhibitor or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claims 1 to 7.

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