CN-122003235-A - Method for treating cardiomyopathy induced by metabolic inflexibility

Abstract

Provided herein are methods of treating, preventing, or delaying the onset of heart diseases such as cardiomyopathy and heart failure by administering a therapeutic compound to a subject in need thereof. The present disclosure also generally relates to methods of using the therapeutic compounds to improve cardiac efficiency in a subject in need thereof. The present disclosure also generally relates to methods of using the therapeutic compounds to inhibit the activity of Pyruvate Dehydrogenase Kinase (PDK) in a subject in need thereof. The therapeutic compound is a compound of formula (I): Or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Inventors

• H. Edlund
• S. Norin
• M. ERIKSSON

Assignees

• 塔吉农有限责任公司

Dates

Publication Date

20260508

Application Date

20240719

Priority Date

20230720

Claims (20)

1. 1. A method of treating a cardiomyopathy associated with metabolic inflexibility in a subject in need thereof, comprising administering an effective amount of a compound having the structure: , or a pharmaceutically acceptable salt, solvate or prodrug thereof.
2. 2. A method of preventing or delaying the onset of cardiomyopathy associated with metabolic inflexibility comprising administering an effective amount of a compound having the structure: , or a pharmaceutically acceptable salt, solvate or prodrug thereof.
3. 3. The method of claim 1 or 2, wherein an alkali metal salt of the compound is administered.
4. 4. A process according to claim 3 wherein the alkali metal salt is a sodium salt.
5. 5. The method of any one of claims 1-4, wherein the cardiomyopathy is a diabetic cardiomyopathy.
6. 6. The method of any one of claims 1-5, wherein the subject has type 1 diabetes.
7. 7. The method of any one of claims 1-5, wherein the subject has type 2 diabetes.
8. 8. The method of any one of claims 1-7, wherein the subject has hypertension.
9. 9. The method of any one of claims 1-8, wherein the administration restores cardiac metabolic flexibility of the subject's heart.
10. 10. The method of any one of claims 1-9, wherein the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof is administered in a pharmaceutical composition.
11. 11. The method of claim 10, wherein the pharmaceutical composition is a tablet or capsule.
12. 12. The method of any one of claims 1-11, wherein the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof is orally administered to the subject once daily at a dose of about 100 mg to about 1,000 mg.
13. 13. The method of claim 12, wherein the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally to the subject once daily at a dose of about 200 mg to about 600 mg.
14. 14. The method of claim 12, wherein the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally to the subject once daily at a dose of about 400 mg to about 800 mg.
15. 15. The method of claim 12, wherein the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally to the subject once daily at a dose of about 400 mg.
16. 16. The method of any one of claims 1-15, wherein the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally to the subject once daily and results in a steady state plasma concentration of the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof of about 70 μg/mL to about 120 μg/mL.
17. 17. The method of any one of claims 1-15, wherein the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally to the subject once daily and results in a steady state plasma concentration of the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof of about 90 μg/mL to about 160 μg/mL.
18. 18. The method of claim 17, wherein the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally to the subject once daily and results in a steady state plasma concentration of the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof of about 100 μg/mL to about 150 μg/mL.
19. 19. The method of claim 17, wherein the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally to the subject once daily and results in a steady state plasma concentration of the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof of about 120 μg/mL to about 140 μg/mL.
20. 20. The method of any one of claims 1-19, wherein the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof is administered orally to the subject once daily and results in a steady state AUC 0-24 of the compound or pharmaceutically acceptable salt, solvate, or prodrug thereof of about 1,500 h x μg/mL to about 4,000 h x μg/mL.

Description

Method for treating cardiomyopathy induced by metabolic inflexibility Cross Reference to Related Applications The present application claims priority from U.S. provisional patent application No. 63/514,700 filed on 7/20, 2023, incorporated herein by reference in its entirety. Reference to an electronic sequence Listing The contents of the electronic sequence Listing (286502000940 SEQLIST. Xml; size: 43,273 bytes; and date of creation: 2024, 7, 18) are incorporated herein by reference in their entirety. Technical Field The present disclosure relates generally to methods of treating, preventing or delaying the onset of heart diseases such as cardiomyopathy and heart failure by administering the compounds provided herein. The present disclosure also generally relates to methods of improving cardiac efficiency using the compounds provided herein. The present disclosure also generally relates to methods of inhibiting the activity of Pyruvate Dehydrogenase Kinase (PDK) using the compounds provided herein. Background AMP-activated protein kinase (AMPK) is a key regulator of energy balance and is activated when metabolic stress is reduced in intracellular adenosine triphosphate (ATP; fasting, hypoxia, ischemia) pools or increased ATP consumption (physical activity/muscle contraction). AMPK is involved in a variety of signaling pathways regulating energy metabolism and consumption. Many of the clinical benefits of exercise or caloric restriction are mediated by increased AMPK activity. Thus, it has become an attractive therapeutic target for a variety of diseases, including cardiovascular metabolic disorders such as obesity and diabetes. The pleiotropic effects of AMPK activation have led to great interest in the development of AMPK activators in a wide range of therapeutic applications, including metabolic diseases such as diabetes and obesity, cardiovascular and renal diseases, inflammatory diseases and aging. Many of these activators interact with allosteric drugs and metabolite (ADaM) sites, which are formed by interactions between the alpha and beta subunits, and their physiological functions are not yet known. Binding allosteric at this site activates AMPK and prevents dephosphorylation. However, the specificity of the activator for the ADaM site varies between different AMPK trimers, and many activators show higher activity on β1-containing complexes than β2. Since β2 is the main subtype of expression in skeletal muscle and liver (two major target organs of metabolic diseases), AMPK activators selective for complexes containing β1 subunits are not ideally suited for the treatment of metabolic diseases. Despite advances in AMPK activators and other cardiovascular metabolic modulators, the incidence of cardiovascular metabolic diseases is continuously rising. Cardiovascular metabolic disorders include a range of conditions such as hypertension, dyslipidemia, obesity, and diabetes. Due to genetic, lifestyle and environmental factors, the response of everyone to treatment may vary greatly. For individuals, these disorders remain progressive conditions leading to significant morbidity and mortality. As the population of western societies ages, these problems are becoming increasingly burdensome. There is an urgent and increasing unmet medical need for therapies and interventions that can affect the incidence and progression of cardiovascular metabolic disorders, including interventions that can mimic the clinical benefits of exercise and caloric restriction. Disclosure of Invention The compound 4-chloro-N- [2- [ (4-chlorophenyl) methyl ] -3-oxo-1, 2, 4-thiadiazol-5-yl ] benzamide has previously been identified as an AMPK activator, which acts primarily by inhibiting dephosphorylation of activated (phosphorylated) AMPK instead of allosterically activating AMPK. Unlike the other AMPK activators discussed above, it was surprisingly observed that 4-chloro-N- [2- [ (4-chlorophenyl) methyl ] -3-oxo-1, 2, 4-thiadiazol-5-yl ] benzamide enhanced glucose uptake without increasing glycogen content. In some aspects, provided herein are methods and compositions for treating and/or preventing heart disease in a subject (e.g., a human patient) by administering a compound of formula (I): (I), Or a pharmaceutically acceptable salt, solvate or prodrug thereof. Further, in other aspects, provided herein are methods of enhancing cardiac efficiency by administering a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, to a subject (e.g., a human). In the foregoing aspect, the subject may be a patient or a healthy subject. The compounds of formula (I) are also known as 4-chloro-N- [2- [ (4-chlorophenyl) methyl ] -3-oxo-1, 2, 4-thiadiazol-5-yl ] benzamide. Surprisingly, it has been found that compounds of formula (I) are capable of restoring cardiac metabolic flexibility in the heart of a subject (e.g., patient) suffering from various cardiac diseases or complications. It has also been found that