Compounds for upregulating utrophin levels in muscle cells and method of application thereof

Abstract

Disclosed herein are compounds for treating and / or managing muscular dystrophy. According to the embodiment of the invention, the compound can inhibit the activity of DPP-IV, so that the muscle nutrition related protein level in muscles is up-regulated, and the integral improvement of muscle functions is realized. Embodiments herein also result in a composition for upregulating muscle nutrition related protein levels in muscle cells.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480036801.5 (22) Application Date 2024.04.11 (30) Priority Data 202341026707 2023.04.11 IN (85) PCT International Application Entering National Phase Date 2025.12.01 (86) PCT International Application Application Data PCT / IN2024 / 050379 2024.04.11 (87) PCT International Application Publication Data WO2024 / 214117 EN 2024.10.17 (71) Applicant: Peptide Intelligence Technology Pte Ltd. Address: Bangalore, Karnataka, India (72) Inventors: A. Boudni, V. Narayanan, S. Narayanan (74) Patent Agency: Shanghai Huacheng Intellectual Property Agency Co., Ltd. 31300 Patent Attorney: Du Juan (51) Int.Cl. A61K 45 / 06 (2006.01) A61P 25 / 00 (2006.01) (54) Invention Title: Compound for Upregulating the Level of Myotrophic Related Proteins in Muscle Cells and Method of Application Thereof (57) Abstract: This document discloses a compound for the treatment and / or management of muscular dystrophy. According to the embodiments described herein, the compound is able to inhibit DPP-IV activity, thereby upregulating the level of myotrophic related proteins in muscles and achieving overall improvement of muscle function. The embodiments described herein also yield a composition for upregulating the level of myotrophic related proteins in muscle cells. Claims (4 pages), Description (13 pages), Drawings (9 pages), CN 121586585 A 2026.02.27 CN 1 21 58 65 85 A 1. A compound or a pharmaceutically acceptable salt thereof, said compound or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating and / or managing muscular dystrophy, wherein said compound is a DPP-IV inhibitor selected from sitagliptin, meglitin, linagliptin, vildagliptin, ticagliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, treagliptin, ocagliptin, ivevogliptin, goxolitin, retaliptin, cofoglitin, futagliptin, prosliptin, and combinations thereof. 2. The compound according to claim 1, wherein said compound is sitagliptin. 3. The compound according to claim 1, wherein said compound is sitagliptin phosphate monohydrate. 4. The compound according to claim 1, wherein the compound is megglitazone.5. The compound of claim 1, wherein the muscular dystrophy is selected from Duchenne muscular dystrophy, Behringer muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emory-Dreyfus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warberg syndrome (WWS), calpain disease or LGMD2A, oculopharyngeal muscular dystrophy, dilated cardiomyopathy associated with DMD (DCM), type 1 triyoshi myopathy (MMD1), and R2 type myomyosin-associated limb-girdle muscular dystrophy (LGMDR2). 6. The compound of claim 1, wherein the compound is administered in combination with at least one other therapy selected from corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy. 7. The compound of claim 6, wherein the corticosteroid therapy comprises administering at least one corticosteroid selected from prednisone, prednisolone, defcodone, varomolorone, and combinations thereof. 8. The compound of claim 6, wherein the exon skipping therapy comprises administering at least one agent selected from etanercept, glomerulone, ASO-based therapies, and combinations thereof. 9. The compound of claim 6, wherein the epigenetic therapy comprises administering at least one agent selected from gemvinosat, pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof. 10. The compound of claim 1, wherein the dosage range of the compound is 10 to 250 mg daily, administered in a single or multiple dosing regimen. 11. The compound of claim 1, wherein the compound is formulated for intravenous, intramuscular, inhalation, intradermal, epidermal, subcutaneous, oral, transdermal, transmucosal, local, intranasal, vaginal, intrathecal, epidural, ocular, or rectal administration. 12. A composition comprising the compound of claim 1 or a pharmaceutically acceptable salt, solvate, or analogue thereof, and optionally at least one pharmaceutically acceptable excipient. 13. The composition of claim 12, wherein the compound is a DPP-IV inhibitor selected from sitagliptin, megliptin, linagliptin, vildagliptin, ticagliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, treagliptin, ocagliptin, ivevogliptin, goxoliplamine, retaliptin, cofoglitazone, futagliptin, prosliptin, and combinations thereof. 14. The composition of claim 12, wherein the compound is sitagliptin.15. The composition of claim 12, wherein the compound is sitagliptin phosphate monohydrate. 16. The composition of claim 12, wherein the pharmaceutically acceptable excipient is selected from mannitol, starch, xylitol, maltodextrin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous dicalcium phosphate, glyceryl behenate, triethyl citrate, polyethylene glycol, croscarmellose sodium cellulose, stearic acid, talc, hydrogenated cottonseed oil, magnesium stearate, colloidal silica, polysorbate, sodium dodecyl sulfate, anhydrous calcium hydrogen phosphate, sodium stearoyl fumarate, propyl gallate, poly(vinyl alcohol), polyethylene glycol 3350, titanium dioxide, iron oxide red, iron oxide yellow, and mixtures thereof. 17. The composition of claim 12, wherein the composition is administered in combination with at least one other therapy selected from corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy. 18. The composition of claim 17, wherein the corticosteroid therapy comprises administering at least one corticosteroid selected from prednisone, prednisolone, defcodone, varomolorone, and combinations thereof. 19. The composition of claim 17, wherein the exon skipping therapy comprises administering at least one agent selected from etanercept, glomerulone, ASO-based therapies, and combinations thereof. 20. The composition of claim 17, wherein the epigenetic therapy comprises administering at least one agent selected from gemvinosat, pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof. 21. The composition of claim 12, wherein the dosage range of the composition is 10 to 250 mg daily, administered in a single or multiple dosing regimen. 22. The composition of claim 12, wherein the composition is formulated for intravenous, intramuscular, inhalation, intradermal, epidermal, subcutaneous, oral, transdermal, transmucosal, local, intranasal, vaginal, intrathecal, epidural, ocular, or rectal administration. 23. A method for treating muscular dystrophy, wherein the method comprises administering a therapeutically effective amount of the compound of claim 1 to a subject in need. 24. The method of claim 23, wherein the compound is administered in combination with at least one other therapy selected from corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy. 25. The method of claim 24, wherein the corticosteroid therapy comprises administering at least one corticosteroid selected from prednisone, prednisolone, defcodone, varomolorone, and combinations thereof.26. The method of claim 24, wherein the exon skipping therapy comprises administering at least one agent selected from etanercept, glomerulone, ASO-based therapies, and combinations thereof. 27. The method of claim 24, wherein the epigenetic therapy comprises administering at least one agent selected from givenoxat, pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof. 28. The method of claim 23, wherein the muscular dystrophy is selected from Duchenne muscular dystrophy, Behringer's muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emory-Dreyfus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warberg syndrome (WWS), calpain disease or LGMD2A, oculopharyngeal muscular dystrophy, dilated cardiomyopathy associated with DMD (DCM), type 1 triyoshi myopathy (MMD1), and R2 type sarcolemma protein-associated limb-girdle muscular dystrophy (LGMDR2). 29. A method for upregulating the level of myotrophic protein-associated proteins in muscle cells, wherein the method comprises administering a therapeutically effective amount of the compound of claim 1 to a subject in need. 30. The method of claim 29, wherein the compound is administered in combination with at least one other therapy selected from corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy. 31. The method of claim 30, wherein the corticosteroid therapy comprises administering at least one corticosteroid selected from prednisone, prednisolone, defcodone, varomollone, and combinations thereof. 32. The method of claim 30, wherein the exon skipping therapy comprises administering at least one agent selected from etanercept, glomerulone, ASO-based therapies, and combinations thereof. 33. The method of claim 30, wherein the epigenetic therapy comprises administering at least one agent selected from gemvinosat, pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof. 34. Use of the compound of claim 1 for the treatment of muscular dystrophy. 35. The use according to claim 34, wherein the compound is a DPP-IV inhibitor selected from sitagliptin, megliptin, linagliptin, vildagliptin, ticagliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, treagliptin, ocagliptin, ivengliptin, gosoletin, retaliptin, cofoglitazone, futagliptin, prosliptin, and combinations thereof.36. The use according to claim 34, wherein the compound is sitagliptin. 37. The use according to claim 34, wherein the compound is sitagliptin phosphate monohydrate. 38. The use according to claim 34, wherein the muscular dystrophy is selected from Duchenne muscular dystrophy, Benedict's muscular dystrophy, Fukuyama-type congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emory-Dreyfus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warberg syndrome (WWS), calpain disease or LGMD2A, oculopharyngeal muscular dystrophy, dilated cardiomyopathy associated with DMD (DCM), triyoshi type 1 myopathy (MMD1), and R2 type myomyosin-associated limb-girdle muscular dystrophy (LGMDR2). 39. The use of claim 34, wherein the compound is administered in combination with at least one other therapy selected from corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy. 40. The use of claim 39, wherein the corticosteroid therapy comprises administering at least one corticosteroid selected from prednisone, prednisolone, defcodone, varomolorone, and combinations thereof. 41. The use of claim 39, wherein the exon skipping therapy comprises administering at least one agent selected from etanercept, glomerulone, ASO-based therapies, and combinations thereof. 42. The use of claim 39, wherein the epigenetic therapy comprises administering at least one agent selected from gemvinosat, pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof. 43. The use of claim 34, wherein the compound is administered in a dose range of 10 to 250 mg daily, in a single or multiple dosing regimen. 44. The use according to claim 34, wherein the compound is formulated for intravenous, intramuscular, inhalation, intradermal, subcutaneous, oral, transdermal, transmucosal, or rectal administration. 45. Use of the compound according to claim 1 for upregulating the levels of myotrophic protein-related proteins in muscle cells. 46. The use according to claim 45, wherein the compound is a DPP-IV inhibitor selected from sitagliptin, meglitin, linagliptin, vildagliptin, ticagliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, treagliptin, ocagliptin, ivengliptin, goxoliplamine, retaliptin, cofoglitin, futagliptin, prosliptin, and combinations thereof. 47. The use according to claim 45, wherein the compound is sitagliptin.48. The use according to claim 45, wherein the compound is sitagliptin phosphate monohydrate. 49. The use according to claim 45, wherein the compound is administered in combination with at least one other therapy selected from corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle-strengthening chemotherapy. 50. The use according to claim 49, wherein the corticosteroid therapy comprises administering at least one corticosteroid selected from prednisone, prednisolone, defcodone, varomolorone, and combinations thereof. 51. The use according to claim 49, wherein the exon skipping therapy comprises administering at least one agent selected from etanercept, glomerulone, ASO-based therapies, and combinations thereof. 52. The use according to claim 49, wherein the epigenetic therapy comprises administering at least one agent selected from gemvinosat, pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof. 53. The use according to claim 45, wherein the dosage range of the compound is 10 to 250 mg daily, administered in a single or multiple dosing regimen. 54. The use according to claim 45, wherein the compound is formulated for intravenous, intramuscular, inhalation, intradermal, subcutaneous, oral, transdermal, transmucosal, or rectal administration. Claims 4 / 4 pages 5 CN 121586585 A Compound for Upregulating the Levels of Myotrophin-Related Proteins in Muscle Cells and Methods of Using Thereof Cross-Reference to Related Applications

[0001] This application is based on and enjoys the benefit of Indian Provisional Application 202341026707, the contents of which are incorporated herein by reference. Technical Field

[0002] The embodiments disclosed herein generally relate to compounds for the treatment or management of muscular dystrophy. More specifically, the present invention relates to DPP-IV inhibitors and their use for upregulating the levels of myotrophin-related proteins in muscle cells to treat muscular dystrophy. Background Art

[0003] Muscular dystrophy (MD) is a group of inherited diseases characterized by skeletal muscle weakness and atrophy. Duchenne muscular dystrophy (DMD) is one of the most common forms of muscular dystrophy, caused by a C-linked recessive mutation in the dystrophin gene. Globally, approximately 1 in 5,000 men has DMD.

[0004] Mutations in the dystrophin gene impair the production of the muscle subtype of dystrophin, an important component of the dystrophin-associated glycoprotein complex (DGC), which is responsible for connecting the internal cytoskeleton and the surrounding extracellular matrix.Dystrophin plays a crucial role in providing structural stability to skeletal muscle, maintaining its strength and flexibility, and protecting the sarcomere from damage caused by muscle contraction. Patients with muscular dystrophy exhibit low or complete absence of dystrophin expression, leading to progressive muscle degeneration and neuromuscular junction disorder. Dystrophin deficiency also results in elevated intracellular calcium levels and excessive nitric oxide production, triggering processes such as protein degradation, free radical generation, oxidative stress, inflammation, fibrosis, necrosis, and macrophage activation, ultimately leading to skeletal muscle dystrophy, respiratory distress, and cardiomyopathy. Progressive muscle degeneration typically results in loss of walking ability between the ages of 8 and 12, and premature death between the ages of 20 and 30 due to respiratory and cardiac complications.

[0005] Despite extensive research into the molecular mechanisms of muscular dystrophy, a complete cure remains elusive, and currently available treatments primarily focus on supportive care. Management of muscular dystrophy relies mainly on symptomatic treatment, including physical therapy and the use of corticosteroids. While corticosteroids can help slow disease progression, they are also associated with some serious side effects, such as weight gain, hyperglycemia, insulin resistance, Cushing's syndrome features, short stature, behavioral changes, osteoporosis, and fractures.

[0006] Treatment strategies for muscular dystrophy have primarily focused on restoring dystrophin expression through various gene therapy approaches, such as antisense oligonucleotide-mediated exon skipping, AAV-mediated miniature dystrophin gene delivery, CRISPR / Cas9 genome editing, and stop codon suppression. However, these approaches are targeted at specific mutations and are limited to a subset of muscular dystrophy patients. Challenges including adverse immune events, toxicity, and the necessity of systemic administration further complicate their application. Therefore, it is crucial to find treatment strategies that can reduce muscle fiber damage and delay the onset of disability in muscular dystrophy patients without being limited by mutation type.

[0007] Upregulation of myotroph-associated protein (an autosomal homolog of dystrophin with structural and functional similarity to dystrophin) offers an alternative treatment approach for muscular dystrophy. Myotrophic-associated proteins (MAs) are expressed in fetal muscle and various non-skeletal muscle tissues in adults, including the lungs, kidneys, and liver. Spontaneous compensatory upregulation of MAs is frequently observed in individuals with muscular dystrophy and in animal models lacking MAs. Pioneering studies in animal models support the potential of MAs as functional substitutes for MAs, demonstrating their feasibility as a treatment for muscular dystrophy.Furthermore, therapeutic interventions that utilize small molecules to increase the levels of myotroph-related proteins in the muscles of individuals with muscular dystrophy rarely trigger immune responses or cause adverse side effects.

[0008] Myotroph-related proteins can be upregulated through various signaling pathways, such as AHR-ARNT, TGF-β, HDAC, GLP-1–PGC-1α, GABPα / β, and calcineurin-NFAT-mediated signaling pathways. Proposed strategies for regulating myotroph-related protein expression include using small molecule drugs to enhance its expression at both the transcriptional and translational levels. However, the long-term effects of myotroph-related protein-focused treatments remain uncertain and require further clinical evaluation. For example, the development of the small molecule drug ezutromid, designed to upregulate myotroph-related proteins, was recently terminated due to failure to meet clinical trial endpoints, possibly due to inherent limitations in the molecule's pharmacokinetic properties. Therefore, there is currently a lack of evidence to suggest the existence of clinically effective therapeutic interventions that upregulate myotroph-related protein levels to treat patients with muscular dystrophy.

[0009] Therefore, there is an urgent need to find therapeutic agents with characteristics of high efficacy, easy administration, broad applicability, and excellent safety and tolerability for the prevention, treatment, and management of muscular dystrophy. Summary of the Invention

[0010] A primary objective of the embodiments herein is to provide a compound for the treatment and / or management of muscular dystrophy.

[0011] Another objective of the embodiments herein is to provide a compound capable of upregulating the levels of muscle-related proteins in muscles.

[0012] Another objective of the embodiments herein is to provide a compound capable of activating muscle regeneration and repair.

[0013] Another objective of the embodiments herein is to provide a compound capable of preventing or delaying muscle wasting or degeneration.

[0014] Another objective of the embodiments herein is to provide a compound capable of reducing inflammation, oxidative stress, fibrosis, and necrosis in muscles.

[0015] Another objective of the embodiments disclosed herein is to provide a compound that is readily available, cost-effective, user-friendly, therapeutically effective, sustainable, rapid, and has minimal side effects.

[0016] Another objective of the embodiments herein is to provide a compound capable of providing potential protection against neuromuscular diseases.

[0017] Another object of the embodiments herein is to provide a compound for preparing a medicament for treating and / or managing muscular dystrophy via the mechanism described above.

[0018] Another object of the embodiments herein is to provide a compound having dipeptidyl peptidase IV (DPP-IV) inhibitor activity for treating and / or managing muscular dystrophy.

[0019] Another object of the embodiments herein is to provide a composition for treating and / or managing muscular dystrophy.

[0020] Another object of the embodiments herein is to provide a method for treating and / or managing muscular dystrophy. Specification 2 / 13 pages 7 CN 121586585 A

[0021] The above-described and other aspects of the embodiments herein will be more fully explained and understood in conjunction with the following description and drawings. However, it should be understood that the following description, while illustrating at least one embodiment and its many specific details, is provided by way of example only and not as a limitation. Many changes and modifications may be made within the scope of the embodiments herein without departing from the spirit of the embodiments herein, and the embodiments herein include all such modifications. Brief Description of the Drawings

[0022] The embodiments herein are illustrated in the accompanying drawings, wherein the same reference numerals denote corresponding parts in the figures. The embodiments herein will be more fully understood by referring to the following illustrative drawings. The embodiments herein are illustrated by example in the drawings, wherein:

[0023] Figure 1 shows the in vitro effect of a DPP-IV inhibitor on the levels of muscular dystrophy-related proteins according to the embodiments disclosed herein.

[0024] Figure 2 shows a comparison of the upregulation of myotrophic proteins in C2C12 mouse skeletal muscle myoblasts by sitagliptin and ezutromid according to the embodiments disclosed herein.

[0025] Figure 3 is a schematic diagram illustrating the experimental protocol for in vivo studies in a D2.mdx mouse DMD model according to the embodiments disclosed herein.

[0026] Figure 4 shows the treadmill test results of D2.mdx mice according to the embodiments disclosed herein, wherein Figure 4A shows the effect of sitagliptin on running distance, and Figure 4B shows the effect of sitagliptin on time to exhaustion.

[0027] Figures 5A and 5B show the effect of sitagliptin according to the embodiments disclosed herein on normalized grip strength in D2.mdx mice before and after the treadmill test, respectively.

[0028] Figures 6A and 6B show the effects of sitagliptin according to the embodiments disclosed herein on the suspension latency of D2.mdx mice before and after the treadmill test, respectively.

[0029] Figure 7 shows the effects of sitagliptin according to the embodiments disclosed herein on the fall latency of D2.mdx mice in the rotarod test.

[0030] Figure 8 shows the effects of sitagliptin according to the embodiments disclosed herein on serum creatine kinase levels in D2.mdx mice.

[0031] Figure 9 shows a summary of the treadmill test on day 28 according to the embodiments disclosed herein, wherein Figure 9A shows the running distance, Figure 9B shows the time to exhaustion, Figure 9C shows the normalized grip strength before the treadmill test, Figure 9D shows the normalized grip strength after the treadmill test, Figure 9E shows the suspension test before the treadmill test, and Figure 9F shows the suspension test after the treadmill test.Detailed Description of Embodiments

[0032] The embodiments herein and their various features and advantages will be explained more fully with reference to the non-limiting embodiments shown in the accompanying drawings and described in detail in the following detailed description. Descriptions of well-known parts and process techniques are omitted to avoid unnecessary confusion with the embodiments herein. The examples used herein are intended only to help understand how the embodiments herein are practiced and to further enable those skilled in the art to practice the embodiments herein. Therefore, these examples should not be construed as limiting the scope of the embodiments herein.

[0033] For the purpose of interpreting this specification, the terminology as defined herein will apply, and where appropriate, singular terms will also include plural terms and vice versa. It should be understood that the terminology used herein is used only to describe particular embodiments and is not intended to be limiting. Unless otherwise stated, the terms “comprising,” “having,” and “including” should be understood as open-ended terms. Specification 3 / 13 pages 8 CN 121586585 A

[0034] The words / phrases “exemplary,” “example,” “illustration,” “in some cases,” “etc.,” “such as,” “for example,” and “i.e.” are used herein only to mean “as an example, instance, or illustration.” For any embodiment or implementation of the subject matter described herein, the use of the words / phrases “exemplary,” “example,” “illustration,” “in some cases,” “etc.,” “such as,” “for example,” “i.e.,” should not necessarily be construed as preferred or superior to other embodiments. Unless otherwise stated, the terms “comprising,” “having,” and “including” should be understood as open-ended terms. The terms “individual,” “patient,” “subject,” or “cell line” are used interchangeably herein.

[0035] It should be noted that the elements in the drawings are used only for the purposes of this specification and to illustrate various aspects of the embodiments disclosed herein. The drawings are intended to help readily understand various technical features, and it should be understood that the embodiments shown herein are not limited to the drawings. Therefore, this disclosure should be understood to extend to any modifications, equivalents, and substitutions other than those specifically listed in the drawings and the corresponding description. The use of terms such as first, second, third, etc., or I, II, III, etc., to describe components / elements / steps is for the purposes of this specification only and should not be construed as a sequence / placement / occurrence unless otherwise stated.

[0036] Embodiments herein disclose compounds for the preparation of medicaments for the treatment and / or management of muscular dystrophy. The inventors of this application have demonstrated for the first time that inhibiting DPP-IV activity can upregulate the levels of myotrophic protein in in vitro mouse skeletal muscle cell lines and in vivo Duchenne muscular dystrophy (DMD) D2-mdx mouse models, thereby achieving overall improvement in muscle function.The inventors further explained that DPP-IV inhibitors commonly used to treat type 2 diabetes (such as sitagliptin, melogliptin, linagliptin, vildagliptin, tenegliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omaglitin, evogliptin, gosogliptin, retagliptin, cofrogliptin, fotagliptin, and prusogliptin) can be reactivated to upregulate myotrophic protein levels in muscle cells and can be used to treat or manage muscular dystrophy. Therefore, embodiments thereof disclose the use of dipeptidyl peptidase IV (DPP-IV) inhibitors for the treatment and / or management of muscular dystrophy. Specifically, the inventors have demonstrated that sitagliptin can upregulate the levels of myotroph-related proteins in muscle cells, thereby achieving an overall improvement in muscle function. Embodiments thereof also provide a composition for upregulating the levels of myotroph-related proteins in muscle cells. According to embodiments thereof, the composition comprises at least one DPP-IV inhibitor or a pharmaceutically acceptable salt, solvate, or analog thereof, and optionally at least one pharmaceutically acceptable excipient.

[0037] The term “muscular dystrophy” refers to a group of rare neuromuscular diseases that are genetically and clinically heterogeneous, caused by mutations in the dystrophin gene, the dysferlin gene, and the associated glycoprotein complex (DAPC / DGC). Muscular dystrophy as used herein includes different types of muscular dystrophy, including but not limited to dystroglycanopathy, dysferlinopathy, and dystrophinopathy.

[0038] Muscular dystrophy proteoglycan disease refers to muscular dystrophy with abnormal glycosylation of α-dystrophy proteoglycan (DG) (a glycoprotein that interacts with dystrophy protein) or gene mutations related to the dystrophy proteoglycan protein complex (DAPC / DGC).The clinical manifestations of muscular dystrophy proteoglycan diseases are wide-ranging, ranging from severe to mild congenital muscular dystrophy, including Fukuyama-type congenital muscular dystrophy (FCMD), myotonic dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy (LGMD, including approximately 32 subtypes, such as LGMDR9 / LGMD2I), Emery-Dreiffus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), calpain disease (or LGMD2A), and oculopharyngeal muscular dystrophy.

[0039] Muscular dystrophy includes a series of X-linked muscle diseases ranging in severity from mild to severe, including Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM).

[0040] Myofascial proteinopathy is a disease caused by a deficiency of myofascial proteins due to mutations in the DYSF gene. Myofascial proteins are membrane proteins in the sarcolemma that participate in various functions, such as membrane repair and vesicle fusion, T-tube development and maintenance, Ca2+ signaling, and the regulation of various molecules. Myofascial proteinopathy includes Miyoshi Myopathy type 1 (MMD1) and R2 myofascial protein-associated limb-girdle muscular dystrophy (LGMDR2). Therefore, the compounds of the present invention can be used to treat and / or manage muscular dystrophy, including but not limited to Fukuyama congenital muscular dystrophy (FCMD), myotonic dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emory-Dreyfus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warberg syndrome (WWS), calpain disease (or LGMD2A), oculopharyngeal muscular dystrophy, Duchenne muscular dystrophy, Behringer muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), type 1 triyoshi myopathy (MMD1), and R2 type myomyosin-associated limb-girdle muscular dystrophy (LGMDR2).

[0041] In one embodiment, the muscular dystrophy is Duchenne muscular dystrophy (DMD). In another embodiment, the muscular dystrophy is Behringer muscular dystrophy (BMD). Both DMD and BMD are characterized by progressive muscle weakness and skeletal degeneration.Muscular dystrophy is almost absent in patients with DMD, while in patients with BMD, the dystrophy content is only 10% to 40% of the normal value. Increased sarcolemma permeability caused by muscular dystrophy usually leads to the release of creatine kinase (CK) from muscle fibers. Therefore, elevated serum CK levels are a marker of muscle damage. CK levels in patients with DMD are significantly elevated compared to the normal range, which has diagnostic value.

[0042] Muscular dystrophy as used herein also includes atrophy characterized by muscle degeneration or loss of mass, usually attributed to aging or various diseases such as poliomyelitis, severe malnutrition, nerve damage, or other neurogenic diseases. Muscular dystrophy usually originates from gene mutations, resulting in severe weakness due to insufficient muscle protein, often accompanied by significant muscle weakness and atrophy. Although atrophy can be alleviated through exercise and lifestyle modifications, muscular dystrophy is irreversible due to its hereditary nature.

[0043] DPP-IV inhibitors as used herein refer to molecules that inhibit the activity of dipeptidyl peptidase IV (DPP-IV) enzyme. DPP-IV is an enzyme expressed on the surface of most cell types and is involved in immune regulation, signal transduction, and apoptosis. DPP-IV enzymes play a major role in glucose metabolism and are responsible for degrading incretins, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptides (or gastric inhibitory peptides, GIPs). DPP-IV enzymes have five binding sites: S1, S2, S1′, S2′, and the S2 extended domain. Primary interactions with S1 and S2 are essential for DPP-IV inhibition, while further interactions with the S1′, S2′, and S2 extended domains may enhance inhibition. Examples of DPP-IV inhibitors include, but are not limited to, sitagliptin, meglitin, linagliptin, vildagliptin, ticagliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, treagliptin, ocagliptin, ivengliptin, goxoliplamine, retaliptin, cofoglitin, futagliptin, and prosliptin.

[0044] DPP-IV inhibitors are classified into classes 1, 2, and 3 based on their interactions with the enzyme. Class 1 inhibitors (e.g., vildagliptin and saxagliptin) bind to S1 and S2, which represent basic inhibitors. Class 2 inhibitors (e.g., alogliptin and linagliptin) interact with other sites (S1′ and S2′), potentially resulting in enhanced inhibition compared to Class 1 inhibitors. Class 3 inhibitors (e.g., sitagliptin and ticagliptin) bind to other sites (S2 extended domain), thereby producing enhanced DPP-IV inhibition. Specification 5 / 13 pages 10 CN 121586585 A

[0045] According to embodiments herein, compounds used to prepare medicaments for treating and / or managing muscular dystrophy include at least one dipeptidyl peptidase IV (DPP-IV) inhibitor, a salt thereof, or a combination thereof.

[0046] In one embodiment, the compound is sitagliptin. Sitagliptin (or (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-amine) and its phosphate are the first FDA-approved oral DPP-IV inhibitors. In one embodiment, the compound is sitagliptin phosphate monohydrate.

[0047] In one embodiment, the compound is megliptin. Megliptin (or (2S,4S)-4-fluoro-1-[2-[[(1R,3S)-3-(1,2,4-triazol-1-ylmethyl)cyclopentyl]amino]acetyl]pyrrolidine-2-nitrile) is a potent, selective, orally bioavailable cyanopyrrolidine DPP-IV inhibitor with hypoglycemic activity.

[0048] In one embodiment, the compound is linagliptin. Linagliptin (or 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione) is an FDA-approved oral antidiabetic drug. Linagliptin differs from other DPP-IV inhibitors in that it has non-linear pharmacokinetic characteristics, is not primarily cleared by the renal system, and has concentration-dependent protein-binding properties.

[0049] In one embodiment, the compound is vildagliptin. Vildagliptin (or (S)-1-[2-(3-hydroxyadamantane-1-ylamino)acetyl]pyrrolidine-2-nitrile) is an FDA-approved oral antidiabetic drug that enhances the pancreatic islet cell response to glucose.

[0050] In one embodiment, the compound is ticagliptin. Tigagliptin (or {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)-1-piperazinyl]-2-pyrrolidinyl}(1,3-thiazolidin-3-yl)methyl ketone) is a newer antidiabetic drug.

[0051] The scope of the invention also includes the use of salts, solvates, derivatives or analogs of sitagliptin, meglitin, linagliptin, vildagliptin, ticagliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, treagliptin, ocagliptin, ivevogliptin, goslgliptin, retaliptin, cofoglitin, futagliptin and proslgliptin.

[0052] Compositions

[0053] Embodiments herein also relate to a composition for the treatment and / or management of muscular dystrophy. In one embodiment, the composition contains at least one DPP-IV inhibitor or a pharmaceutically acceptable salt, solvate, or analogue thereof.DPP-IV inhibitors include, but are not limited to, sitagliptin, meglitin, linagliptin, vildagliptin, ticagliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, treagliptin, ocagliptin, ivevogliptin, goxolizumab, retaliptin, cofliptin, futagliptin, and prosliptin.

[0054] In one embodiment, the composition contains a pharmaceutically acceptable salt of a DPP-IV inhibitor. As used herein, a pharmaceutically acceptable salt refers to a salt that retains the bioavailability of the free acid and free base of a particular compound and has no adverse biological or other properties. A pharmaceutically acceptable salt may also refer to a salt that may have unexpectedly superior bioavailability or bioavailability compared to the actual or active pharmaceutical ingredient (API). According to the invention, a pharmaceutically acceptable salt is made from an acidic inorganic or acidic organic compound, or a basic inorganic or basic organic compound. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts, etc. Solid salts can exist in various crystal structures and can also exist as hydrates. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, salts of substituted amines (including naturally occurring substituted amines), salts of cyclic amines, and salts of basic ion exchange resins (such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucose, histidine, halamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.). Salts of inorganic and organic acids include acetates, benzenesulfonates, benzoates, camphorsulfonates, citrates, ethanesulfonates, fumarates, gluconates, glutamates, hydrobromide, hydrochlorides, hydroxyethanesulfonates, lactates, maleates, malates, mandelates, mesylates, mucilages, nitrates, dihydroxynaphthyl salts, pantothenates, phosphates, succinates, sulfates, tartrates, p-toluenesulfonates, etc. In one embodiment, a pharmaceutically acceptable salt is a phosphate. In one embodiment, the composition contains a pharmaceutically acceptable salt of sitagliptin. In one embodiment, the composition contains sitagliptin phosphate monohydrate.

[0055] In one embodiment, the composition comprises a solvate or the like of a DPP-IV inhibitor. A solvate as used herein generally refers to a combination of a compound (or its salt) with a solvent (e.g., water). Representative examples include hydrates, hemihydrates, trihydrates, etc.As used herein, the term "analogue" generally refers to a compound whose chemical structure is substantially similar to that of a parent compound while retaining at least some of the biological functions of the parent compound. Analogues also include pharmaceutically acceptable salts.

[0056] In one embodiment, the composition comprises at least one pharmaceutically acceptable excipient. Examples of pharmaceutically acceptable excipients include, but are not limited to, mannitol, starch, xylitol, maltodextrin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous dicalcium phosphate, glyceryl behenate, triethyl citrate, polyethylene glycol, croscarmellose sodium, stearic acid, talc, hydrogenated cottonseed oil, magnesium stearate, colloidal silica, polysorbate, sodium lauryl sulfate, anhydrous calcium hydrogen phosphate, sodium stearoyl fumarate, propyl gallate, poly(vinyl alcohol), polyethylene glycol 3350, titanium dioxide, iron oxide red, iron oxide yellow, or mixtures thereof. In one embodiment, the composition may further comprise a pharmaceutically acceptable carrier, diluent, and / or adjuvant. Within the scope of the invention, the composition may also comprise other additives selected from solvents, stabilizers, or suspensions.

[0057] The composition may be formulated together with or separately from a pharmaceutically acceptable excipient or carrier. Preferably, the compounds of the invention are formulated together with a pharmaceutically acceptable excipient or carrier for simultaneous or near-simultaneous administration. In one embodiment, the pharmaceutically acceptable excipient or carrier may be formulated separately from the compounds of the invention.

[0058] The concentration range of the DPP-IV inhibitor in the composition may be from as low as 0.1% to as high as 100% of the total composition. In some embodiments, the concentration of the DPP-IV inhibitor in the composition is from 1% to 90% (by weight). In some embodiments, the concentration of the DPP-IV inhibitor in the composition is from 5% to 80% (by weight). In some embodiments, the concentration of the DPP-IV inhibitor in the composition is from 10% to 70% (by weight). The specific amount depends on any other materials selected.

[0059] According to embodiments herein, a DPP-IV inhibitor or a composition containing at least one DPP-IV inhibitor may be administered as a monotherapy or in combination with one or more other therapies. In one embodiment, a DPP-IV inhibitor or a composition containing a DPP-IV inhibitor is administered as a monotherapy. In one embodiment, a DPP-IV inhibitor or a composition containing a DPP-IV inhibitor is administered as a combination therapy with one or more other therapeutic agents. Non-limiting examples of other therapies that may be used in combination therapy include, but are not limited to, corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy.

[0060] In one embodiment, the combination therapy comprises administration of a DPP-IV inhibitor or a composition containing at least one DPP-IV inhibitor with a corticosteroid. Corticosteroid therapy comprises administration of corticosteroids to delay the progression of muscular dystrophy. Corticosteroids used to treat muscular dystrophy include, but are not limited to, prednisone / prednisolone, deflazacort (an oxazoline derivative of prednisolone), vamorolone, and combinations thereof. There are two commonly used regimens for administering corticosteroids: daily administration and intermittent administration.

[0061] In one embodiment, the combination therapy comprises administration of a DPP-IV inhibitor or a composition containing at least one DPP-IV inhibitor with exon skipping therapy. Exon skipping therapy refers to the use of antisense oligonucleotides to excise selected exons from the precursor mRNA at or near the mutation site, thereby generating a translatable transcript from the muscular dystrophy protein gene mutant. Antisense oligonucleotides (AONs) are 20-30 nucleotides in length and are designed to target specific precursor mRNA sequences and skip specific DMD exons flanking the mutated region, thereby producing in-frame truncated transcripts that can be translated into functional dystrophin proteins. AON agents used for exon skipping therapy include, but are not limited to, eterisen, golodirsen, viltolarsen, casimersen, drisapersen, tricyclic DNA (tcDNA), antisense oligonucleotide (ASO)-based therapies, and combinations thereof.

[0062] In one embodiment, the combination therapy comprises administration of a DPP-IV inhibitor or a composition containing at least one DPP-IV inhibitor with an epigenetic agent. Epigenetic therapy involves using small molecules or epigenetic modifiers to modify gene activity without altering the gene's coding sequence. Key epigenetic mechanisms, such as DNA methylation or histone modification, play an important role in regulating muscle regeneration. Epigenetic therapies include treatments that target specific chromatin elements in a single signaling pathway by designing epigenetic drugs. Examples of epigenetic drugs include, but are not limited to, givinostat, trogostatin A (TSA), ubiquitin deacetylase (HDAC) inhibitors, HDAC6 inhibitors, and combinations thereof.

[0063] In one embodiment, the combination therapy includes administration of a DPP-IV inhibitor or a composition containing at least one DPP-IV inhibitor with a gene therapy drug.Gene therapy includes, but is not limited to, adeno-associated virus (AAV) vector-mediated gene therapy, in which the micromuscular dystrophy protein gene is a preferred candidate gene.

[0064] The scope of the invention also includes the combined use of DPP-IV inhibitors or compositions containing at least one DPP-IV inhibitor with muscle regeneration therapies (e.g., AAK1 inhibitors or cAMP enhancement mechanisms), other myotrophic protein upregulators, muscle strengthening therapies (e.g., aryl hydrocarbon receptor (AhR) antagonists, myostatin inhibitors, muscle Ca2+ overload inhibitors (e.g., P2X7 antagonists), calcium pool manipulated calcium influx (SOCE) / calcium release activated calcium (CRAC) channel inhibitors, anti-inflammatory agents acting on NF-κB pathway signaling targets (e.g., NF-κB inhibitors, IKK2 / β inhibitors, TBK1 inhibitors, Akt-mTOR pathway inhibitors), and anti-fibrotic mechanism pathway agents (e.g., TGF-β inhibitors, RIPK1 / 3 inhibitors, activin receptor inhibitors, Smad2 / 3 inhibitors, TAK1 inhibitors, and other GLP-1 agonists) and GLP-1 pathway activators.

[0065] The combination therapy is administered in a manner and dosage that effectively increases the production of myotrophic proteins and improves muscle function and strength.

[0066] The DPP-IV inhibitors of the present invention, or compositions comprising at least one DPP-IV inhibitor, can be used in combination with one or more other drugs for the treatment, inhibition, or improvement of muscular dystrophy, wherein the combination of drugs is safer or more effective than single use. Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention via the usual route and dosage. When the compounds of the present invention are used simultaneously with one or more other drugs, the pharmaceutical composition preferably contains such other drugs in addition to the compounds of the present invention. Therefore, the pharmaceutical compositions of the present invention include pharmaceutical compositions containing one or more other active ingredients in addition to the compounds of the present invention. Combination therapy may also include therapy in which the compounds of the present invention are administered with one or more other drugs in different overlapping dosing regimens. Furthermore, when used in combination with one or more other active ingredients, the dosage of the compounds of the present invention and other active ingredients may be lower than the dosage when used alone.

[0067] According to embodiments herein, DPP-IV inhibitors, or compositions comprising at least one DPP-IV inhibitor, can be formulated for administration via any suitable route, including parenteral (e.g., intravenous, intramuscular), intradermal, epidermal, subcutaneous, It can be administered orally, transdermally, transmucosally, topically, intranasally, vaginally, intrathecally, epidurally, ocularly, or rectally, or by injection or inhalation.Instructions for Use, Page 8 / 13, CN 121586585 A

[0068] Solutions or suspensions for parenteral, intradermal, or subcutaneous application may contain the following components: sterile diluents, such as water for injection, saline solution, fixative oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; antimicrobial agents, such as benzyl alcohol or methylparaben; antioxidants, such as ascorbic acid or sodium bisulfite; chelating agents, such as ethylenediaminetetraacetic acid; buffers, such as acetate, citrate, or phosphate; and agents for adjusting osmotic pressure, such as sodium chloride or dextrorotatory glucose. The pH value may be adjusted with an acid or base (e.g., hydrochloric acid or sodium hydroxide). Parenteral preparations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

[0069] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (water-soluble) or dispersants, as well as sterile powders for the ad hoc preparation of sterile injectable solutions or dispersants. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor EL.™ (BASF, Pasipani, NJ), or phosphate-buffered saline (PBS). In all cases, the composition is preferably sterile and should have easily injectable flowability. In some embodiments, it should remain stable under manufacturing and storage conditions and be resistant to contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, or liquid polyethylene glycol), and suitable mixtures thereof. Appropriate flowability can be maintained, for example, by using a coating (e.g., lecithin), or for dispersants by maintaining the desired particle size, or by using, for example, a surfactant. Microbial action can be prevented by adding various antimicrobial and antifungal agents (e.g., parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc.). In many cases, the composition preferably contains an isotonic agent, such as sugar, polyol (e.g., mannitol or sorbitol), or sodium chloride. The absorption of the injectable composition can be delayed by adding a delayed-absorption agent (e.g., aluminum monostearate or gelatin) to the composition.

[0070] The sterile injection solution can be prepared by adding the required amount of the active compound and one or more of the ingredients as described above (if necessary) to a suitable solvent, followed by filtration for sterilization. Typically, the dispersant is prepared by adding the active compound to a sterile carrier containing an alkaline dispersion medium and other desired ingredients as described above. For sterile powders used to prepare the sterile injection solution, preferred preparation methods are vacuum drying and freeze drying, both of which produce powders of the active ingredient and any other desired ingredients from a previously sterile filtered solution.

[0071] DPP-IV inhibitors or compositions containing DPP-IV inhibitors may be formulated as tablets, hard capsules or soft capsules, chewing gums, syrups, elixirs, pills, lozenges, emulsions, dispersible powders or granules, liquids, gels, aqueous or oily suspensions, patches, nanoformulations, or other forms suitable for oral, parenteral, topical, or inhalation administration. Tablets, pills, capsules, lozenges, etc., may contain any of the following ingredients or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, Primogel, or corn starch; lubricants, such as magnesium stearate or sterotes; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring. Suitable tablets can be obtained, for example, by mixing at least one compound usable in this invention with known excipients (e.g., diluents such as microcrystalline cellulose, calcium carbonate, calcium phosphate, or lactose; disintegrants such as croscarmellose sodium, hydroxypropyl methylcellulose (HPMC), or sodium hydroxymethyl starch; binders such as starch or gelatin, guar gum, or xanthan gum; lubricants such as magnesium stearate or talc and / or pharmaceuticals). Shapes include round, capsule-shaped, flat, oval, and beveled (with or without embossing).

[0072] Capsules containing compounds usable in this invention (e.g., hard or soft gelatin) can be prepared, for example, by mixing the active compound with an inert carrier (e.g., lactose or sorbitol) and filling it into a gelatin capsule. The capsules can be embossed or unembossed.

[0073] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. To provide a palatable oral formulation, sweeteners and flavoring agents as described above may be added. These compositions may be preserved by adding antioxidants (e.g., ascorbic acid).

[0074] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide an active ingredient mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Examples of suitable dispersants or wetting agents and suspending agents have been described above. Other excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0075] The composition may also be in the form of an oil-in-water emulsion. The oil phase can be vegetable oil (such as olive oil or peanut oil), mineral oil (such as liquid paraffin), or a mixture thereof.Suitable emulsifiers may be naturally occurring gums, such as gum arabic or tragacanth; naturally occurring phospholipids, such as soybean phospholipids or lecithin; and esters or metaesters derived from fatty acids and hexitan anhydrides, such as sorbitan monooleate; and condensation products of said metaesters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

[0076] Syrups and elixirs may be formulated with sweeteners (e.g., glycerin, propylene glycol, sorbitol, or sucrose). Such formulations may also contain modifiers, preservatives, flavoring agents, and coloring agents.

[0077] Systemic administration may also be administered via transmucosal or transdermal routes. For transmucosal or transdermal administration, a permeabilizer suitable for the target barrier may be used in the formulation. Such permeabilizers are well known in the art and include, for example, detergents, bile salts, and fusidic acid derivatives for transmucosal administration. Transmucosal administration may be performed via nasal sprays or suppositories. The compounds can be prepared as suppositories (e.g., using conventional suppository bases, such as cocoa butter and other glycerides) or retention enemas for rectal administration.

[0078] The dosage of a DPP-IV inhibitor or a composition containing a DPP-IV inhibitor will vary depending on the specific compound used, the metabolic stability and duration of action of the compound, the route and time of administration, the rate of excretion, the duration of treatment, the severity of the condition, the combination of drugs, the type of any other therapeutic compound administered, the age, weight, general health, sex, diet, body type, and species of the subject (e.g., a human patient). Generally, the dosage of the DPP-IV inhibitor in the compositions of the present invention is the lowest dose that effectively produces the desired effect with no or minimal side effects. The effective dose of the DPP-IV inhibitor can also be administered at appropriate intervals throughout the day in sub-dose doses of 2, 3, 4, 5, 6 or more times. Suitable dose levels are generally about 10 to 250 mg per day, which can be administered once or multiple times. Preferably, the dose level is about 0.5 to about 100 mg / kg per day. Suitable dosage levels may be about 0.01 to 250 mg / kg, about 0.05 to 100 mg / kg, or about 0.1 to 50 mg / kg daily. Within this range, the dosage may be 0.05 to 0.5 mg / kg, 0.5 to 5 mg / kg, or 5 to 50 mg / kg daily. For oral administration, the composition is preferably provided in tablet form containing 1.0 to 1000 mg of active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 mg of active ingredient, adjusted according to symptoms for the patient to be treated.The compound can be administered 1 to 4 times daily (preferably once or twice daily). In one embodiment, the composition is administered in mice at a dose of 30 mg / kg to 70 mg / kg daily. In one embodiment, the composition is administered in D2.mdx mice at a dose of 50 mg / kg daily. In one embodiment, a wider human dose of the composition is 10 to 250 mg daily, administered in a single or multiple dosing regimen.

[0079] In one embodiment, a DPP-IV inhibitor or a composition containing a DPP-IV inhibitor is used to treat and / or manage muscular dystrophy. Treatment or management includes suppressing the condition (i.e., preventing the development or progression of clinical symptoms) and / or alleviating the condition (even if clinical symptoms subside). According to the embodiments described herein, the composition can be used to manage symptoms of muscular dystrophy, such as muscle weakness and atrophy, and can be used to delay disease progression. The composition can also be used to improve the quality of life of patients with muscular dystrophy. In one embodiment, the composition provides a strategy for a specific therapy for muscular dystrophy, as described in page 10 / 13 of this specification, CN 121586585 A. This strategy is applicable in principle to all patients, i.e., not limited to a limited subgroup of patients with mutation-specific muscular dystrophy.

[0080] In one embodiment, a DPP-IV inhibitor or a composition containing a DPP-IV inhibitor upregulates the expression of myotrophic proteins in muscle cells. The expression of myotrophic proteins is regulated at multiple steps in their synthesis and degradation pathways. Different methods of regulating myotrophic protein expression include, but are not limited to, direct mechanisms (e.g., gene or protein substitution) and indirect mechanisms (e.g., transcriptional upregulation of myotrophic protein promoters, post-transcriptional regulation, and protein / mRNA stabilization). Myotrophic proteins can be upregulated through a variety of signaling pathways, but are not limited to, for example, AHR-ARNT, TGF-β, HDAC, GLP-1-PGC-1α, GABPα / β, and calcineurin-NFAT-mediated signaling pathways. In one embodiment, the composition upregulates the expression of myotrophic proteins by inhibiting DPP-IV.

[0081] In one embodiment, a DPP-IV inhibitor or a composition containing a DPP-IV inhibitor activates the PI3K / Akt signaling pathway, which is known to play a role in muscle growth and regeneration. The DPP-IV inhibitor activates the PI3K / Akt signaling pathway in muscle cells, thereby increasing protein synthesis and muscle fiber size. Another mechanism by which the composition works against muscular dystrophy is through stimulation of mitochondrial biosynthesis. In one embodiment, the composition upregulates myogenic factors, such as myogenin (MyoG) and MyoD. In one embodiment, the composition inhibits inflammatory and muscle atrophy factors, thereby reducing muscle atrophy. In one embodiment, the composition can reduce muscle fibrosis and necrosis.In one embodiment, the composition has shown potential therapeutic effects in animal models and clinical trials, demonstrating its effectiveness in humans.

[0082] Using DPP-IV inhibitors as repurposed drugs to upregulate the expression of myotrophic-related proteins has several advantages. DPP-IV inhibitors are potent, well-tolerated, and orally bioavailable drugs with broad applicability, excellent safety and tolerability, making them suitable for long-term use. DPP-IV inhibitors have been shown to be safe for long-term use in children (adolescents) and adults. DPP-IV inhibitors also exhibit anti-inflammatory and anti-fibrotic properties, as well as the ability to prevent muscle atrophy and degradation while enhancing muscle fibers.

[0083] Embodiments herein also disclose a method for increasing the expression of myotrophic-related proteins in a subject of need, comprising administering to the subject a therapeutically effective amount of a DPP-IV inhibitor or a composition comprising at least one DPP-IV inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0084] Embodiments herein also disclose a method for treating muscular dystrophy. According to embodiments herein, the method comprises administering to a subject in need a therapeutically effective amount of a DPP-IV inhibitor or a composition comprising at least one DPP-IV inhibitor or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The terms “effective” or “therapeutically effective” as used herein refer to an amount of compound that is non-toxic but present in an amount sufficient to provide the desired effect in any medical treatment with a reasonable benefit / risk ratio. The desired effect may be relief of signs, symptoms, or causes of disease, or any other desired biological symptom outcome.

[0085] Typically, the subject is a mammal, preferably a human (male or female), whose dipeptidyl peptidase IV enzymatic activity needs to be inhibited. In one embodiment, the subject includes a mammal suffering from muscular dystrophy. In one embodiment, muscular dystrophy includes Fukuyama-type congenital muscular dystrophy (FCMD), myotonic dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emory-Dreyfus muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warberg syndrome (WWS), calpasesin disease (or LGMD2A), oculopharyngeal muscular dystrophy, Duchenne muscular dystrophy, Behringer muscular dystrophy, dilated cardiomyopathy associated with DMD (DCM), type 1 triyoshi myopathy (MMD1), and R2 type sarcolemma protein-associated limb-girdle muscular dystrophy (LGMDR2).

[0086] The present invention will be further described with reference to the following embodiments, which are for illustrative purposes only and should not be construed as limiting the scope of the embodiments disclosed herein.It will be apparent to those skilled in the art that various modifications can be made to the materials and methods without departing from the scope of the embodiments claimed in this specification, page 11 / 13, CN 121586585 A.

[0087] Example 1 – In vitro upregulation of myotrophic proteins by DPP-IV inhibitors

[0088] C2C12 myoblasts were seeded in wells containing growth medium (10% FBS and DMEM). After the cells reached 70% confluence, they were added to differentiation medium (2% HS and DMEM) and differentiated for 7 days. Stock solutions of sitagliptin and other DPP-IV inhibitors (i.e., megliptin, linagliptin, vildagliptin, and ticagliptin) were prepared in DMSO. The cells were treated with stock solutions to a final concentration of 10 µM for 24 hours. RNA was extracted using a Qiagen assay kit, and the upregulation of myotrophic proteins was quantified using Nanodrop RT-PCR.

[0089] Figure 1 shows the fold changes in myotrophic protein expression at a concentration of 10 µM for sitagliptin, meglitin, linagliptin, vildagliptin, and ticagliptin. Clearly, all DPP-IV inhibitors upregulated myotrophic protein levels in myoblasts.

[0090] Example 2 – Comparison of Sitagliptin and Ezutrimeline for In Vitro Upregulation of Myotrophic Proteins

[0091] Using the same experimental protocol as in Example 1, C2C12 myoblasts were treated with sitagliptin for 24 hours. Ezutrimeline, a known upregulator of myotrophic proteins, was used as a positive control. RNA extraction and RT-PCR were performed to quantify the fold changes in myotrophic protein mRNA expression. Figure 2 shows the fold changes in myotrophic protein mRNA expression in C2C12 mouse skeletal muscle myoblasts compared to 10 μM ezutrimeline. Sitagliptin showed a higher upregulation of myotrophic proteins compared to ezutrimeline.

[0092] Example 3 – In vivo study of the D2.mdx mouse model

[0093] Dosage and efficacy evaluation protocol:

[0094] All functional experimental parameters were evaluated in wild-type mice with a background of mdx and D2.mdx mice (D2.B10-DMD mdx / J mice, obtained from Jackson Laboratory (strain number 013141), Bar Harbor, Maine, USA, 04609).

[0095] The test substance (sitagliptin 50 mg / kg) was administered orally once daily (qd) at a dose volume of 10 mL / kg. Sitagliptin was suspended in a formulation containing 0.1% Tween 20 and 0.5% carboxymethyl cellulose (CMC) and administered orally once daily for 28 days.Wild-type and MDX control groups received only the carrier (0.5% carboxymethyl cellulose (CMC) containing 0.1% Tween20). Animal weight was recorded twice weekly / daily before the study (before administration) and throughout the study. Clinical signs, mortality, and morbidity were also monitored.

[0096] Experimental procedures and efficacy evaluation:

[0097] D2.mdx mice and wild-type mice were trained on a treadmill device (Pan Lab, Harvard Instruments, USA) for functional testing, and their baseline (day 0) performance on the treadmill device (running distance and time to exhaustion) was recorded. Based on their weight and treadmill functional parameters, D2.mdx mice were randomly assigned to the MDX control group and the MDX sitagliptin group.

[0098] All three groups of mice (wild-type, DMD-control, and DMD-sitagliptin) underwent functional tests at week 0 (baseline-day 0), week 2 (day 14), and at the end of the study (week 4 or day 28). Muscle function was assessed using grip strength tests (using a grip strength meter (Orchid Scientific, model: GSM02RS, India)), suspension tests, treadmill running, and rotarod tests (Orchid Scientific, India) after treatment with the carrier and sitagliptin (50 mg / kg, orally). Blood samples were collected 30 minutes after the treadmill functional test on days 0, 14, and 28 for creatine kinase (CK) analysis. The efficacy of sitagliptin was assessed by comparing functional test parameters and serum CK levels in the treatment and mdx control groups with baseline values ​​in the wild-type group.

[0099] Statistical analysis was performed using GraphPad Prism version 10 software. Two-way ANOVA (multiple comparisons) was used, followed by Tukey's / Bonferroni 't' test. Where applicable in the figures, significance compared to DMD-control (vector treatment) is indicated, and the instructions are on pages 12 / 13, CN 121586585 A.

[0100] Figure 3 shows the experimental protocol used for in vivo studies in the D2.mdx mouse model. The D2.mdx mouse is an excellent DMD model that reproduces several human characteristics of DMD muscle pathology, such as lower hind limb muscle weight, fewer muscle fibers, increased fibrosis and fat accumulation, and muscle weakness (relative to strains with this mutant allele in other genetic backgrounds). Six- to seven-week-old D2.mdx mice were selected for 28 days of in vivo studies.Three groups of animals were selected, with 10 mice in each group: Group I contained wild-type mice, Group II contained D2.mdx control mice, and Group III contained D2.mdx mice treated with sitagliptin (the test substance). Mice in all groups underwent 3 days of training (baseline, day 3) and randomization, followed by 28 days of treatment (days 0–28). Treadmill, grip strength, suspension, rotarod, and creatine kinase tests were recorded on days 0, 14, and 28. The treadmill test was performed on a mouse treadmill (Pan Lab, Harvard Instruments, USA). The rotarod test was used to record parameters for overall improvement in muscle coordination.

[0101] According to the embodiments disclosed herein, Figure 4 shows the results of the D2.mdx mouse treadmill test, wherein Figure 4A shows the effect of sitagliptin on running distance within 30 minutes, and Figure 4B shows the effect of sitagliptin on time to exhaustion. The results showed that sitagliptin significantly and persistently improved running distance and time to exhaustion during 28 days of treatment.

[0102] Figures 5A and 5B show the effects of sitagliptin according to the embodiments disclosed herein on normalized grip strength in D2.mdx mice before and after the treadmill test, respectively. Before the treadmill stress, the grip strength of the sitagliptin-treated mice was comparable to that of wild-type mice. The suspension test also showed that the performance of the sitagliptin-treated mice was comparable to that of wild-type mice, regardless of whether they experienced treadmill stress (Figures 6A and 6B). The fall latency in the rotarod test showed that the mice treated with sitagliptin exhibited persistent improvement in overall muscle coordination (Figure 7).

[0103] Elevated serum creatine kinase (CK) levels in blood samples are an indicator of muscle degeneration caused by muscular dystrophy. Serum creatine kinase levels were measured within 30 minutes after the mice underwent the treadmill test. The pattern of creatine kinase changes in mdx control mice was consistent with published literature. Figure 8 shows a significant reduction in serum creatine kinase levels during the 28-day treatment period with sitagliptin.

[0104] Figures 9A-9F provide a summary of running distance, time to exhaustion, normalized grip strength before and after the treadmill test, and suspension test before and after the treadmill test on day 28 in the D2.mdx mouse model. Compared with control mice with DMD, mice treated with sitagliptin showed significant improvements in all functional parameters. This significant performance improvement indicates an overall improvement in muscle function. These functional results suggest that sitagliptin has potential application value in the treatment of DMD.

[0105] The above description of the specific embodiments will fully reveal the general nature of the embodiments described herein, thereby enabling others to easily modify and / or adapt these specific embodiments for various applications by applying existing knowledge without departing from the general concept. Therefore, such modifications and alterations should be understood and intended to be understood as falling within the meaning and scope of equivalent embodiments of the disclosed embodiments.It should be understood that the words or terms used herein are for descriptive purposes only and are not intended to be limiting. Therefore, although embodiments thereof have been described herein by way of examples and implementations, those skilled in the art will recognize that the embodiments and implementations disclosed herein can be practiced with modifications within the scope of the embodiments described herein. Instruction Manual Page 13 / 13 18 CN 121586585 A Figure 1 Instruction Manual Appendix 1 / 9 Page 19 CN 121586585 A Figure 2 Figure 3 Instruction Manual Appendix 2 / 9 Page 20 CN 121586585 A Figure 4A Figure 4B Instruction Manual Appendix 3 / 9 Page 21 CN 121586585 A Figure 5A Figure 5B Instruction Manual Appendix 4 / 9 Page 22 CN 121586585 A Figure 6A Figure 6B Instruction Manual Appendix 5 / 9 Page 23 CN 121586585 A Figure 7 Figure 8 Instruction Manual Appendix 6 / 9 Page 24 CN 121586585 A Figure 9A Figure 9B Instruction Manual Appendix 7 / 9 Page 25 CN 121586585 A Figure 9C Figure 9D Instruction Manual Appendix 8 / 9 Page 26 CN 121586585 A Figure 9E Figure 9F Instruction Manual Appendix 9 / 9 Page 27 CN 121586585 A.

Claims

1. A compound or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment and / or management of muscular dystrophy, wherein, The compound is a DPP-IV inhibitor selected from the group consisting of sitagliptin, metformin, linagliptin, vildagliptin, trelagliptin, saxagliptin, anagliptin, alogliptin, gemigliptin, teneligliptin, omarigliptin, evogliptin, gosogliptin, remogliflozin, klfogliptin, fetogliptin, prosotril, and combinations thereof.

2. The compound of claim 1, wherein, The compound is sitagliptin.

3. The compound of claim 1, wherein, The compound is sitagliptin phosphate monohydrate.

4. The compound of claim 1, wherein, The compound is metformin.

5. The compound of claim 1, wherein, The compound is a DPP-IV inhibitor selected from the group consisting of sitagliptin, metformin, linagliptin, vildagliptin, trelagliptin, saxagliptin, anagliptin, alogliptin, gemigliptin, teneligliptin, omarigliptin, evogliptin, gosogliptin, remogliflozin, klfogliptin, fetogliptin, prosotril, and combinations thereof.

6. The compound of claim 1, wherein, The compound is sitagliptin.

7. The compound of claim 6, wherein, The compound is sitagliptin phosphate monohydrate.

8. The compound of claim 6, wherein, The compound is metformin.

9. The compound of claim 6, wherein, The compound is a DPP-IV inhibitor selected from the group consisting of sitagliptin, metformin, linagliptin, vildagliptin, trelagliptin, saxagliptin, anagliptin, alogliptin, gemigliptin, teneligliptin, omarigliptin, evogliptin, gosogliptin, remogliflozin, klfogliptin, fetogliptin, prosotril, and combinations thereof.

10. The compound of claim 1, wherein, The compound is sitagliptin.

11. The compound of claim 1, wherein, The compound is sitagliptin phosphate monohydrate. The compound is metformin.

13. The composition of claim 12, wherein, The compound is administered in a dose ranging from 10 to 250 mg per day, in a single or multiple dosing regimen.

14. The composition of claim 12, wherein, The compound is formulated for intravenous, intramuscular, inhalation, intradermal, epidermal, subcutaneous, oral, transdermal, transmucosal, topical, intranasal, vaginal, intrathecal, epidural, ocular, or rectal administration.

15. The composition of claim 12, wherein, 12. A composition comprising the compound of claim 1, or a pharmaceutically acceptable salt, solvate, or analog thereof, and optionally at least one pharmaceutically acceptable excipient. The compound is a DPP-IV inhibitor selected from the group consisting of sitagliptin, metformin, linagliptin, vildagliptin, trelagliptin, saxagliptin, anagliptin, alogliptin, gemigliptin, teneligliptin, omarigliptin, evogliptin, gosogliptin, remogliflozin, klfogliptin, fetogliptin, prosotril, and combinations thereof. The compound is sitagliptin. The compound is sitagliptin phosphate monohydrate. The compound is metformin.

16. The composition of claim 12, wherein, The pharmaceutically acceptable excipient is selected from mannitol, starch, xylitol, maltodextrin, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, anhydrous dicalcium phosphate, glyceryl behenate, triethyl citrate, polyethylene glycol, croscarmellose sodium, stearic acid, talc, hydrogenated cottonseed oil, magnesium stearate, colloidal silicon dioxide, polysorbate, sodium lauryl sulfate, anhydrous dibasic calcium phosphate, sodium stearyl fumarate, propyl gallate, poly(vinyl alcohol), polyethylene glycol 3350, titanium dioxide, iron oxide red, iron oxide yellow, and mixtures thereof.

17. The composition of claim 12, wherein, The composition is administered in combination with at least one other therapy selected from corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regenerative therapy, and muscle strengthening therapy.

18. The composition of claim 17, wherein, The corticosteroid therapy comprises administration of at least one corticosteroid selected from prednisone, prednisolone, deflazacort, valrmodilone, and combinations thereof.

19. The composition of claim 17, wherein, The exon skipping therapy comprises administration of at least one agent selected from eteplirsen, golodirsen, ASO-based therapies, and combinations thereof.

20. The composition of claim 17, wherein, The epigenetic therapy comprises administration of at least one agent selected from givinostat, pan-HDAC inhibitor, HDAC6 inhibitor, and combinations thereof.

21. The composition of claim 12, wherein, The composition is administered in a dosage ranging from 10 to 250 mg per day, in a single or multiple dosing regimen.

22. The composition of claim 12, wherein, The composition is formulated for intravenous, intramuscular, inhalation, intradermal, epidermal, subcutaneous, oral, transdermal, transmucosal, topical, intranasal, vaginal, intrathecal, epidural, ocular, or rectal administration.

23. A method for treating muscular dystrophy, wherein, The method comprises administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1.

24. The method of claim 23, wherein, The composition is administered in combination with at least one other therapy selected from corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regenerative therapy, and muscle strengthening therapy.

25. The method of claim 24, wherein, The corticosteroid therapy comprises administration of at least one corticosteroid selected from prednisone, prednisolone, deflazacort, valrmodilone, and combinations thereof.

26. The method of claim 24, wherein, The exon skipping therapy comprises administration of at least one agent selected from eteplirsen, golodirsen, ASO-based therapies, and combinations thereof.

27. The method of claim 24, wherein, The epigenetic therapy comprises administration of at least one agent selected from givinostat, pan-HDAC inhibitor, HDAC6 inhibitor, and combinations thereof.

28. The method of claim 23, wherein, The muscular dystrophy is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), calpainopathy or LGMD2A, oculopharyngeal muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), Miyoshi myopathy (MMD1), and limb girdle muscular dystrophy R2 (LGMDR2).

29. A method for upregulating the level of a myostatin-related protein in muscle cells, wherein, The method comprises administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1.

30. The method of claim 29, wherein, The compound is administered in combination with at least one other therapy selected from corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppression therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy.

31. The method of claim 30, wherein, The corticosteroid therapy comprises administering at least one corticosteroid selected from prednisone, prednisolone, deflazacort, valrmetasone, and combinations thereof.

32. The method of claim 30, wherein, The exon skipping therapy comprises administering at least one agent selected from eteplirsen, golodirsen, ASO-based therapy, and combinations thereof.

33. The method of claim 30, wherein, The epigenetic therapy comprises administering at least one agent selected from givinostat, pan-HDAC inhibitor, HDAC6 inhibitor, and combinations thereof.

34. Use of the compound of claim 1 for the treatment of muscular dystrophy.

35. The use of claim 34, wherein, The compound is a DPP-IV inhibitor selected from sitagliptin, metformin, linagliptin, vildagliptin, trelagliptin, saxagliptin, anagliptin, alogliptin, gemigliptin, teneligliptin, omarigliptin, evogliptin, gosogliptin, remogliflozin, kewiride, faltagliptin, prosotagliptin, and combinations thereof.

36. The use of claim 34, wherein, The compound is sitagliptin.

37. The use of claim 34, wherein, The compound is sitagliptin phosphate monohydrate.

38. The use of claim 34, wherein, The muscular dystrophy is selected from Duchenne muscular dystrophy, Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb girdle muscular dystrophy, Emery-Dreifuss muscular dystrophy (EDMD), muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), calpainopathy or LGMD2A, oculopharyngeal muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), Miyoshi myopathy (MMD1), and limb girdle muscular dystrophy R2 (LGMDR2).

39. The use of claim 34, wherein, The compound is administered in combination with at least one other therapy selected from corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppression therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy.

40. The use of claim 39, wherein, The corticosteroid therapy comprises administration of at least one corticosteroid selected from the group consisting of prednisone, prednisolone, deflazacort, valmetasone, and combinations thereof.

41. The use of claim 39, wherein, The exon skipping therapy comprises administration of at least one agent selected from the group consisting of eteplirsen, golodirsen, ASO-based therapies, and combinations thereof.

42. The use of claim 39, wherein, The epigenetic therapy comprises administration of at least one agent selected from the group consisting of givinostat, pan-HDAC inhibitor, HDAC6 inhibitor, and combinations thereof.

43. The use of claim 34, wherein, The compound is administered in a dosage range of 10 to 250 mg per day, in a single or multiple dosing regimen.

44. The use of claim 34, wherein, The compound is formulated for intravenous, intramuscular, inhalation, intradermal, subcutaneous, oral, transdermal, transmucosal, or rectal administration.

45. Use of the compound of claim 1 for upregulating levels of utrophin in muscle cells.

46. The use of claim 45, wherein, The compound is a DPP-IV inhibitor selected from the group consisting of sitagliptin, metformin, linagliptin, vildagliptin, trelagliptin, saxagliptin, anagliptin, alogliptin, gemigliptin, teneligliptin, omarigliptin, evogliptin, gosogliptin, remogliflozin, alogliptin, tofacitinib, and combinations thereof.

47. The use of claim 45, wherein, The compound is sitagliptin.

48. The use of claim 45, wherein, The compound is sitagliptin phosphate monohydrate.

49. The use of claim 45, wherein, The compound is administered in combination with at least one other therapy selected from the group consisting of corticosteroid therapy, gene therapy, exon skipping therapy, immunosuppressive therapy, epigenetic therapy, muscle regeneration therapy, and muscle strengthening therapy.

50. The use of claim 49, wherein, The corticosteroid therapy comprises administration of at least one corticosteroid selected from the group consisting of prednisone, prednisolone, deflazacort, valmetasone, and combinations thereof.

51. The use of claim 49, wherein, The exon skipping therapy comprises administration of at least one agent selected from the group consisting of eteplirsen, golodirsen, ASO-based therapies, and combinations thereof.

52. The use of claim 49, wherein, The epigenetic therapy comprises administration of at least one agent selected from the group consisting of givinostat, pan-HDAC inhibitor, HDAC6 inhibitor, and combinations thereof.

53. The use of claim 45, wherein, The compound is administered in a dosage range of 10 to 250 mg per day, in a single or multiple dosing regimen.

54. The use of claim 45, wherein, The compound is formulated for intravenous, intramuscular, inhalation, intradermal, subcutaneous, oral, transdermal, transmucosal, or rectal administration.

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