Compounds for upregulating eutrophin levels in muscle cells and methods for their application.

Abstract

Compounds for the treatment or management of muscular dystrophy, or both, are disclosed herein. Compounds according to the embodiments herein can inhibit DPP-IV activity, thereby upregulating muscle eutrophin levels and resulting in an overall improvement in muscle function. Embodiments herein also achieve compositions for upregulating eutrophin levels in muscle cells.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of Indian Provisional Application No. 202341026707, the content of which is incorporated herein by reference in its entirety.

[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 for up - regulating the level of myotrophin in muscle cells for the treatment of muscular dystrophy and their use.

Background Art

[0003] Muscular dystrophy (MD) is a group of hereditary diseases characterized by the weakness and degeneration of skeletal muscles. Duchenne muscular dystrophy (DMD) is one of the most common forms of muscular dystrophy caused by an X - chromosome - linked recessive mutation in the dystrophin gene. DMD affects approximately 1 in 5000 males worldwide.

[0004] Mutations in the dystrophin gene prevent the production of a key component of the dystrophin-associated glycoprotein complex (DGC), a muscle isoform of dystrophin that helps bridge the internal cytoskeleton with the surrounding extracellular matrix. Dystrophin plays a crucial role in providing structural stability to skeletal muscle, maintaining strength and flexibility, and protecting the muscle sheath from damage induced by muscle contraction. Individuals with dystrophy exhibit either low levels of dystrophin expression or a complete absence of dystrophin expression, leading to progressive muscle degeneration and destruction of neuromuscular junction tissue. Dystrophin deficiency also results in elevated intracellular calcium levels and excessive nitric oxide production, initiating processes such as proteolysis, free radical generation, oxidative stress, inflammation, fibrosis, necrosis, and macrophage activation, ultimately leading to skeletal muscular dystrophy, respiratory failure, and cardiomyopathy. Progressive muscle degeneration, often resulting in loss of walking ability within 8–12 years and death within 20–30 years, is common due to respiratory and cardiac complications.

[0005] Despite extensive research into the molecular mechanisms of muscular dystrophy, a comprehensive treatment for the disease remains unclear, and currently available therapies primarily offer only supportive care. Management of muscular dystrophy relies mainly on symptomatic treatment, including physiotherapy and the use of corticosteroids. While corticosteroids may help slow disease progression, they are associated with serious side effects such as weight gain, hyperglycemia, insulin resistance, Cushing's-like characteristics, short stature, behavioral changes, osteoporosis, and fractures.

[0006] Treatment strategies for muscular dystrophy primarily focus on restoring dystrophin expression using various gene therapy methods, including antisense oligonucleotide-mediated exon skipping, AAV-mediated mini-dystrophin gene delivery, CRISPR / Cas9 genome editing, and stop codon suppression. However, these approaches are mutation-specific and limited to only a subset of dystrophy patients. Challenges, including concerns about immunological adverse events, toxicity, and the need for systemic delivery, further complicate their use. Therefore, it is crucial to identify therapeutic strategies that can mitigate muscle fiber damage and delay the onset of disability in muscular dystrophy patients, regardless of the type of mutation.

[0007] Upregulation of eutrophin, an autosomal homolog of dystrophin that shares structural and functional similarities, offers an alternative therapeutic approach for treating muscular dystrophy. Utrophin is expressed in fetal muscle, as well as in various non-skeletal muscle tissues in adults, including the lungs, kidneys, and liver. Spontaneous compensatory upregulation of eutrophin is frequently observed in individuals with muscular dystrophy, as well as in animal models lacking dystrophin. Groundbreaking studies conducted in animal models support the potential of eutrophin as a functional substitute for dystrophin and suggest its viability as a therapeutic approach for treating muscular dystrophy. Furthermore, therapeutic interventions utilizing small molecules to increase eutrophin levels in the muscles of individuals with muscular dystrophy are unlikely to trigger immune responses or cause adverse side effects.

[0008] Utrophin can be upregulated by various signaling pathways, including AHR-ARNT, TGF-β, HDAC, GLP-1-PGC-1α, GABPα / β, and calcineurin-NFAT-mediated signaling pathways. Proposed strategies for modulating utrophin expression include the use of small molecule drugs to enhance its expression at both the transcriptional and translational levels. However, the long-term effects of utrophin-focused therapeutic approaches remain uncertain and require further clinical evaluation. For example, the development program for ezthromide, a small molecule drug designed to upregulate utrophin, was recently terminated because it failed to meet its endpoints in clinical trials, possibly due to the molecule's self-limiting pharmacokinetic profile. Therefore, there is currently a lack of evidence regarding the availability of therapeutic interventions to clinically upregulate utrophin levels to effectively treat patients with muscular dystrophy.

[0009] Therefore, it is absolutely essential to identify therapeutic agents that possess high efficacy, ease of administration, broad applicability, and excellent safety and tolerability profiles for the prevention, treatment, and management of muscular dystrophy. [Overview of the project] [Problems that the invention aims to solve]

[0010] The primary objective of the embodiments herein is to provide compounds for the treatment or management of muscular dystrophy, or both.

[0011] Another object of the embodiments described herein is to provide compounds that can upcontrol muscle eutrophin levels.

[0012] Another object of the embodiments described herein is to provide compounds that can activate muscle regeneration and repair.

[0013] Another object of the embodiments described herein is to provide compounds that can prevent or delay muscle wasting or muscle breakdown.

[0014] Another object of the embodiments described herein is to provide compounds that can reduce muscle inflammation, oxidative stress, fibrosis, and necrosis.

[0015] Another object of the embodiments disclosed herein is to provide compounds that are readily available, cost-effective, easy to use, therapeutically effective, sustainable, rapid, and have minimal side effects.

[0016] Another object of the embodiments described herein is to provide compounds that confer potential protection against neuromuscular diseases.

[0017] Another object of the embodiments described herein is to provide compounds for preparing drugs for the treatment or management of muscular dystrophy or both, via the mechanism described above.

[0018] Another object of the embodiments described herein is to provide compounds having dipeptidyl peptidase IV (DPP-IV) inhibitory activity for the treatment or management of muscular dystrophy or both.

[0019] Another object of the embodiments herein is to provide compositions for the treatment or management of muscular dystrophy or both.

[0020] Another object of the embodiments described herein is to provide a method for the treatment or management of muscular dystrophy or both.

[0021] These and other aspects of the embodiments of this specification will be better understood when considered in conjunction with the following description and the accompanying drawings. However, it should be understood that the following description is given by way of illustration and not limitation, showing at least one embodiment and many of its specific details. Without departing from the spirit of the embodiments of this specification, many changes and modifications can be made within the scope of the embodiments of this specification, and the embodiments of this specification include all such modifications.

[0022] The embodiments of this specification are shown in the accompanying drawings, and throughout the drawings, like reference characters indicate corresponding parts of the various figures. The embodiments of this specification will be better understood from the following description when referring to the following exemplary drawings. The embodiments of this specification are shown as examples of the accompanying drawings.

Brief Description of the Drawings

[0023] [Figure 1] Disclosed herein are embodiments that present the effect of a DPP-IV inhibitor on in vitro levels of utrophin. [Figure 2] Disclosed herein are embodiments that present a comparison of the upregulation of utrophin by sitagliptin and exetromil in C2C12 mouse skeletal muscle myoblasts. [Figure 3] A schematic diagram showing a protocol for in vivo studies in the D2.mdx mouse model of DMD, according to the embodiments disclosed herein. [Figure 4A] Showing the results of the treadmill test in D2.mdx mice, and presenting the effect of sitagliptin on the distance traveled, according to the embodiments disclosed herein. [Figure 4B] Showing the results of the treadmill test in D2.mdx mice, and presenting the effect of sitagliptin on the endurance time, according to the embodiments disclosed herein. [Figure 5A] Disclosed herein are embodiments that present the effect of sitagliptin on the normalized grip strength in D2.mdx mice before treadmill exercise. [Figure 5B] Disclosed herein are embodiments that present the effect of sitagliptin on normalized grip strength in D2.mdx mice after treadmill exercise. [Figure 6A] Disclosed herein are embodiments that present the effect of sitagliptin on hanging latency in D2.mdx mice before treadmill exercise. [Figure 6B] Disclosed herein are embodiments that present the effect of sitagliptin on hanging latency in D2.mdx mice after treadmill exercise. [Figure 7] Disclosed herein are embodiments that present the effect of sitagliptin on the fall latency of D2.mdx mice from the rotarod test. [Figure 8] Disclosed herein are embodiments that present the effect of sitagliptin on the serum creatine kinase level of D2.mdx mice. [Figure 9A] Disclosed herein are embodiments that present a summary of the 28th day of the treadmill test according to the disclosed embodiments, showing the distance traveled. [Figure 9B] Disclosed herein are embodiments that present a summary of the 28th day of the treadmill test according to the disclosed embodiments, showing the tolerance time. [Figure 9C] Disclosed herein are embodiments that present a summary of the 28th day of the treadmill test according to the disclosed embodiments, showing the normalized grip strength before treadmill exercise. [Figure 9D] Disclosed herein are embodiments that present a summary of the 28th day of the treadmill test according to the disclosed embodiments, showing the normalized grip strength after treadmill exercise. [Figure 9E] Disclosed herein are embodiments that present a summary of the 28th day of the treadmill test according to the disclosed embodiments, showing the hanging test before treadmill exercise. [Figure 9F] Disclosed herein are embodiments that present a summary of the 28th day of the treadmill test according to the disclosed embodiments, showing the hanging test after treadmill exercise.

Mode for Carrying Out the Invention

[0024] The embodiments described herein, as well as their various features and advantageous details, are more fully described with reference to the non-limiting embodiments shown in the accompanying drawings and detailed in the following description. Descriptions of well-known components and processing techniques are omitted to avoid unnecessarily obscuring the embodiments herein. The examples used herein are intended solely to facilitate understanding of how the embodiments herein may be carried out and to further enable those skilled in the art to implement the embodiments herein. Therefore, the examples should not be construed as limiting the scope of the embodiments herein.

[0025] For the purposes of interpreting this specification, the definitions (as defined herein) apply, and where appropriate, a term used in the singular also includes the plural, and vice versa. It should be understood that the terms used herein are intended solely to describe and not to limit specific embodiments. The terms “comprising,” “having,” and “including” should be interpreted as non-exclusive unless otherwise specified.

[0026] The words / phrases “exemplary,” “example,” “illustration,” “in one instance,” “and the like,” “and so on,” “etc.,” “etcetera,” “e.g.,” and “i.e.,” are used herein to mean simply “to serve as an example, example, or illustration.” Any embodiment or representation of the subject matter described herein using the words / phrases “exemplary,” “example,” “illustration,” “in one instance,” “and the like,” “and so on,” “etc.,” “etcetera,” “e.g.,” and “i.e.,” should not necessarily be construed as preferable or advantageous to other embodiments. The terms “comprising,” “having,” and “including” should be construed as non-restrictive unless otherwise specified. The terms “individual,” “patient,” “subject,” and “cell lineage” are used herein to be interchangeable.

[0027] It should be noted that the elements in the drawings are shown for the purposes of this specification and to facilitate understanding of the aspects of the embodiments disclosed herein. The accompanying drawings are used to help facilitate understanding of various technical features, and it should be understood that the embodiments presented herein are not limited by the accompanying drawings. Accordingly, this disclosure should be construed to extend to any modifications, equivalents, and substitutes in addition to those specifically described in the accompanying drawings and corresponding descriptions. 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 description and should not be construed as a sequential ordering / arrangement / occurrence unless specifically designated.

[0028] Embodiments of this specification disclose compounds for preparing pharmaceuticals for the treatment or management of muscular dystrophy or both. The inventors of this application have for the first time shown that inhibiting DPP-IV activity can upregulate eutrophin levels in vitro in mouse skeletal muscle cell lines and in vivo in a mouse D2-mdx model of Duchenne muscular dystrophy (DMD), resulting in an overall improvement in muscle function. The inventors have further illustrated that DPP-IV inhibitors, such as sitagliptin, melogliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omaligliptin, evogliptin, gosogliptin, letagliptin, coflogliptin, fotagliptin, and prusogliptin, which are typically used to treat type 2 diabetes, can be used off-target to upregulate eutrophin levels in muscle cells and can be used in the treatment or management of muscular dystrophy. Accordingly, embodiments herein disclose the use of dipeptidyl peptidase-IV (DPP-IV) inhibitors for the treatment or management of muscular dystrophy or both. Specifically, the inventors have shown that sitagliptin can upregulate eutrophin levels in muscle cells, resulting in an overall improvement in muscle function. Embodiments of this specification also achieve compositions for upregulating eutrophin levels in muscle cells. Compositions according to embodiments of this specification comprise at least one DPP-IV inhibitor or a pharmaceutically acceptable salt, solvate, or analog thereof, and optionally at least one pharmaceutically acceptable excipient.

[0029] The term "muscular dystrophy" refers to a rare neuromuscular disorder of a genetically and clinically heterogeneous group caused by mutations in the dystrophin gene, dysferlin gene, and related glycoprotein complex (DAPC / DGC). As used herein, muscular dystrophy encompasses, but is not limited to, different categories of muscular dystrophy, including dystroglycanopathy, dysferlinopathy, and dystrophinopathy.

[0030] Dystroglycanopathy is a general term for muscular dystrophy characterized by abnormal glycosylation of α-dystroglycan (DG), a glycoprotein that interacts with dystrophin, or mutations in genes related to the dystroglycan protein complex (DAPC / DGC). Dystroglycanopathy exhibits a broad clinical spectrum, ranging from severe congenital muscular dystrophy to milder forms, including Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy (approximately 32 variants of LGMD, including LGMDR9 / LGMD2I), Emery-Dreyfus muscular dystrophy (EDMD), myo-ophthalmic-brain disease (MEB), Walker-Warburg syndrome (WWS), calpain opathies, or LGMD2A and oculopharyngeal muscular dystrophy.

[0031] Dystrophinopathy encompasses a range of X-linked muscle diseases, from mild to severe, including Duchenne muscular dystrophy, Becker muscular dystrophy, and dilated cardiomyopathy (DCM) associated with dysmuscular dystrophy (DMD).

[0032] Dysferlinopathy is a disease caused by dysferlin deficiency resulting from mutations in the DYSF gene. Dysferlin is a membrane protein in the muscle sheath that plays a role in membrane repair and vesicle fusion, T tubule development and maintenance, and Ca 2+Dysferlinopathy is involved in various functions, including signal transduction and the regulation of various molecules. Dysferlinopathy includes Miyoshi muscular dystrophy type 1 (MMD1) and limb-girdle muscular dystrophy R2 dysferlin-related (LGMDR2). Therefore, the compounds of the present invention can be used for the treatment or management, or both, of muscular dystrophy, such as, but not limited to, Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emery-Dreyfus muscular dystrophy (EDMD), myo-ophthalmoencephalopathy (MEB), Walker-Warburg syndrome (WWS), calpain opathies or LGMD2A, oculopharyngeal muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), Miyoshi muscular dystrophy type 1 (MMD1), and limb-girdle muscular dystrophy R2 dysferlin-associated (LGMDR2) muscular dystrophy.

[0033] In one embodiment, the muscular dystrophy is Duchenne muscular dystrophy (DMD). In another embodiment, the muscular dystrophy is Becker muscular dystrophy (BMD). Both DMD and BMD are characterized by progressive muscle weakness and skeletal degeneration. In DMD patients, dystrophin is virtually absent, while in BMD patients it is 10% to 40% of the normal level. Increased permeability of the muscle sheath caused by dystrophy often leads to the release of creatine kinase (CK) from muscle fibers. Therefore, elevated serum CK levels are a prominent feature of muscle damage. In patients with DMD, CK is significantly elevated compared to the normal range, which has a diagnostic value.

[0034] As used herein, muscular dystrophy also includes atrophy characterized by muscle degeneration or loss of mass, often resulting from aging or various diseases, such as polio, severe malnutrition, nerve damage, or other neurogenic disorders. Dystrophy is typically caused by gene mutations and is accompanied by severe weakness due to insufficient muscle protein, often with visible muscle weakness and wasting. While atrophy can be mitigated through exercise and lifestyle adjustments, dystrophy, being of a genetic nature, is irreversible.

[0035] DPP-IV inhibitors, as used herein, refer to molecules that inhibit the activity of the dipeptidyl peptidase-IV (DPP-IV) enzyme. DPP-IV is an enzyme expressed on the surface of most cell types and is involved in immunoregulation, signaling, and apoptosis. The DPP-IV enzyme plays a major role in glucose metabolism and is responsible for the degradation of incretins such as glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (or gastric suppressor polypeptide, GIP). The DPP-IV enzyme has five extensive binding sites, namely S1, S2, S1', S2', and S2. Primary interactions with S1 and S2 are important for DPP-IV inhibition, while further interactions at extensive sites of S1', S2', and S2 may enhance inhibition. Examples of DPP-IV inhibitors include, but are not limited to, sitagliptin, melogliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omaligliptin, evogliptin, gosogliptin, letagliptin, coflogliptin, fotagliptin, and prusogliptin.

[0036] DPP-IV inhibitors are classified into Class 1, Class 2, and Class 3 based on their interaction with the enzyme. Class 1 inhibitors, such as vildagliptin and saxagliptin, bind to S1 and S2 and represent basic inhibitory activity. Class 2 inhibitors (e.g., alogliptin and linagliptin) interact with additional sites (S1' and S2') and may result in increased inhibition compared to Class 1. Class 3 inhibitors (e.g., sitagliptin and teneligliptin) broadly bind to the additional site S2, resulting in broader DPP-IV inhibition.

[0037] Compounds for preparing a medicament for the treatment or management of muscular dystrophy or both, according to embodiments herein, comprise at least one dipeptidyl peptidase-IV (DPP-IV) inhibitor, a salt thereof, or a combination thereof.

[0038] 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]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine and its phosphate are the first oral DPP-IV inhibitors approved by the FDA. In one embodiment, the compound is sitagliptin phosphate monohydrate.

[0039] In one embodiment, the compound is melogliptin. Melogliptin, or (2S,4S)-4-fluoro-1-[2-[[(1R,3S)-3-(1,2,4-triazole-1-ylmethyl)cyclopentyl]aminoacetyl]pyrrolidine-2-carbonitrile, is a potent, selective, and orally bioavailable cyanopyrrolidine-based DPP-IV inhibitor with hypoglycemic activity.

[0040] In one embodiment, the compound is linagliptin. Linagliptin, or 8-[(3R)-3-aminopiperidine-1-yl]-7-(buta-2-in-1-yl)-3-methyl-1-[(4-methylquinazoline-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 a nonlinear pharmacokinetic profile, is not primarily excreted by the renal system, and follows concentration-dependent protein binding.

[0041] In one embodiment, the compound is vildagliptin. Vildagliptin, or (S)-1-[2-(3-hydroxyadamantan-1-ylamino)acetyl]pyrrolidine-2-carbonitrile, is an FDA-approved oral antidiabetic agent that enhances the pancreatic islet cell response to glucose.

[0042] In one embodiment, the compound is teneligliptin. Teneligliptin, or {(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazole-5-yl)-1-piperazinyl]-2-pyrrolidinyl}(1,3-thiazolidinedione-3-yl)methanone, is one of the new antidiabetic drugs.

[0043] The use of salts, solvates, derivatives, or analogs of sitagliptin, melogliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omaligliptin, evogliptin, gosogliptin, letagliptin, coflogliptin, fotagliptin, and prusogliptin is also within the scope of the present invention.

[0044] composition Embodiments of this specification also achieve compositions for the treatment or management of muscular dystrophy or both. In one embodiment, the composition contains at least one DPP-IV inhibitor or a pharmaceutically acceptable salt, solvate, or analog thereof. Examples of DPP-IV inhibitors include, but are not limited to, sitagliptin, melogliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omaligliptin, evogliptin, gosogliptin, letagliptin, coflogliptin, fotagliptin, and prusogliptin.

[0045] In one embodiment, the composition contains a pharmaceutically acceptable salt of a DPP-IV inhibitor. A pharmaceutically acceptable salt, as used herein, refers to a salt that retains the biological efficacy of the free acid and free base of a particular compound and is not biologically or otherwise undesirable. A pharmaceutically acceptable salt may also refer to a salt that may have unexpectedly superior biological effects or efficacy compared to an active or effective pharmaceutical ingredient (API). According to the present invention, pharmaceutically acceptable salts are prepared from acidic inorganic or organic compounds, or alkaline inorganic or organic compounds. Examples of salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese salts, manganese, potassium, sodium, and zinc. Salts in solid form may exist in two or more crystalline structures or in hydrate form. Examples of salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as salts of arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine. Examples of salts from inorganic and organic acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. In one embodiment, the 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.

[0046] In one embodiment, the composition comprises a solvate or analogue of a DPP-IV inhibitor. As used herein, a solvate typically refers to a compound (or a salt thereof) associated with a solvent such as water. Typical examples include hydrates, hemihydrates, and trihydrates. As used herein, the term "analog" is typically used to describe a compound having a chemical structure substantially similar to that of the parent compound, while retaining at least some of the biological functions of the parent compound. Analogues also include pharmaceutically acceptable salts.

[0047] 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, hydroxypropylcellulose, ethylcellulose, 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 calcium hydrogen phosphate, sodium stearyl fumarate, propyl gallate, poly(vinyl alcohol), macrogol 3350, titanium dioxide, red iron oxide and yellow iron oxide, or mixtures thereof. In one embodiment, the composition may further comprise a pharmaceutically acceptable carrier, diluent, and / or adjuvant. It is also within the scope of the present invention that the composition may have additional additives selected from solvents, stabilizers, or suspensions.

[0048] The composition may be formulated together with or separately from a pharmaceutically acceptable excipient or carrier. Preferably, the compound of the present invention and the pharmaceutically acceptable excipient or carrier are formulated together for their simultaneous or near-simultaneous administration. In one embodiment, the pharmaceutically acceptable excipient or carrier may be formulated separately from the compound of the present invention.

[0049] The concentration of the DPP-IV inhibitor in the composition can range from a low concentration of about 0.1% of the total amount of the composition to a high concentration of about 100%. In some embodiments, the concentration of the DPP-IV inhibitor in the composition is 1% to 90% by weight. In some embodiments, the concentration of the DPP-IV inhibitor in the composition is 5% to 80% by weight. In some embodiments, the concentration of the DPP-IV inhibitor in the composition is 10% to 70% by weight. The exact amount depends on any additional materials selected.

[0050] The DPP-IV inhibitors or compositions comprising at least one DPP-IV inhibitor according to the embodiments herein may be administered as monotherapy or in combination with one or more additional therapies. In one embodiment, the DPP-IV inhibitor or the composition comprising a DPP-IV inhibitor is administered as monotherapy. In one embodiment, the DPP-IV inhibitor or the composition comprising a DPP-IV inhibitor is administered as combination therapy with one or more additional therapeutic agents. Non-limiting examples of additional 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.

[0051] In one embodiment, combination therapy involves administering a DPP-IV inhibitor or a composition containing at least one DPP-IV inhibitor together with a corticosteroid. Corticosteroid therapy involves administering corticosteroids to slow the progression of muscular dystrophy. Examples of corticosteroids used to treat dystrophy include, but are not limited to, prednisone / prednisolone, deflazacort (an oxazoline derivative of prednisolone), vamorolone, and combinations thereof. Corticosteroids are administered in two common regimens (daily and intermittently).

[0052] In one embodiment, the combination therapy involves administering a DPP-IV inhibitor or a composition containing at least one DPP-IV inhibitor together with exon skipping therapy. Exon skipping therapy refers to the use of antisense oligonucleotides to excise selected exons from the mutated site or adjacent pre-mRNA to produce a translatable transcript from the dystrophin gene mutant. Antisense oligonucleotides (AONs) are 20-30 nucleotides long and are designed to target specific pre-mRNA sequences and skip specific DMD exons adjacent to the mutated region to produce an in-frame but cleaved transcript that translates the functional dystrophin protein. Examples of AONs for exon skipping therapy include, but are not limited to, eteplirsen, golodyrsen, viltolarsen, casimersen, dorysapersen, tricyclo-DNA (tcDNA), ASO-based therapies, and combinations thereof.

[0053] In one embodiment, combination therapy involves administering a DPP-IV inhibitor or a composition containing at least one DPP-IV inhibitor together with an epigenetic agent. Epigenetic therapy involves utilizing small molecules or epigenetic modifiers to modify gene activity without altering the gene coding sequence. Key epigenetic mechanisms, such as DNA methylation or histone modification, play a crucial role in regulating muscle regeneration. Epigenetic therapy includes therapeutic approaches by creating epigenetic drugs designed to target specific chromatin elements within individual signaling pathways. Examples of epigenetic drugs include, but are not limited to, divinostat, trichostatin A (TSA), Pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof.

[0054] In one embodiment, the combination therapy involves administering a DPP-IV inhibitor or a composition containing at least one DPP-IV inhibitor together with the gene therapy agent. Gene therapy includes, but is not limited to, adeno-associated virus (AAV) vector-mediated gene therapy, with the microdystrophin gene being a preferred candidate.

[0055] Muscle regeneration therapies, such as AAK1 inhibitors or cAMP-enhancing mechanisms, other eutrophin upregulators, muscle strengthening therapies, such as aryl hydrocarbon receptor (AhR) antagonists, myostatin inhibitors, P2X7 antagonists, etc. 2+ It is also within the scope of the present invention to use a composition comprising a DPP-IV inhibitor or at least one DPP-IV inhibitor in combination with overload inhibitors, store-operated calcium entry (SOCE) / calcium-release activated calcium (CRAC) channel inhibitors, anti-inflammatory agents acting on NF-κB pathway signaling targets such as NF-κB inhibitors, anti-fibrotic pathway agents such as IKK2 / β inhibitors, TBK1 inhibitors, Akt-mTOR pathway inhibitors, and TGF-β inhibitors, RIPK1 / 3 inhibitors, activin receptor inhibitors, Smad2 / 3 inhibitors, and TAK1 inhibitors, as well as other GLP-1 agonists and GLP-1 pathway activators.

[0056] The combination therapy is administered in a manner and dosage effective in increasing eutrophin production and improving muscle function and strength.

[0057] 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 in the treatment, suppression, or improvement of muscular dystrophy, and the combination of drugs used together is safer or more effective than either drug alone. Such other (one or more) drugs may be administered concurrently or sequentially with the compound of the present invention, in the routes and amounts commonly used for that purpose. When the compound of the present invention is used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compound of the present invention. Combination therapy may also include therapies in which the compound of the present invention and one or more other drugs are administered in different overlapping schedules. When used in combination with one or more other active ingredients, it is also intended that the compound of the present invention and the other active ingredients may be used at lower doses than when each is used alone.

[0058] The DPP-IV inhibitors or compositions comprising at least one DPP-IV inhibitor according to the embodiments herein can be formulated for administration by any suitable route, including parenteral (e.g., intravenous, intramuscular), intradermal, cutaneous, subcutaneous, oral, transdermal, transmucosal, topical, transnasal, transvaginal, intrathecal, epidural, transocular, and rectal administration, or by injection or inhalation.

[0059] Solutions or suspensions used for parenteral, intradermal, or subcutaneous administration may contain the following components: sterile diluents, e.g., water for injection, physiological saline, fixative oil, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antimicrobial agents, e.g., benzyl alcohol or methylparaben; antioxidants, e.g., ascorbic acid, sodium bisulfite; chelating agents, e.g., ethylenediaminetetraacetic acid; buffers, e.g., acetates, citrates, or phosphates; and agents for adjusting isotonicity, e.g., sodium chloride or dextrose. pH can be adjusted with an acid or base such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be sealed in glass or plastic ampoules, disposable syringes, or multi-dose vials.

[0060] Pharmaceutical compositions suitable for injection include sterile aqueous solutions (if water-soluble) or dispersions, and sterile powders for the immediate preparation of sterile injection solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor® EL. (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition is preferably sterile and should be fluid enough to allow for easy syringe injection. In some embodiments, the composition is stable under manufacturing and storage conditions and preserved against microbial contamination such as bacteria and fungi. The carrier may 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. Adequate fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, or by the use of a surfactant. Prevention of microbial action can be achieved by incorporating various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal. In many cases, it is preferable to include isotonic agents, such as sugars, polyalcohols, such as mannitol or sorbitol, or sodium chloride in the composition. Sustained absorption of the injectable composition can be achieved by including absorption-delaying agents, such as aluminum monostearate or gelatin, in the composition.

[0061] Sterile injectable solutions can be prepared by incorporating the required amount of active compound, along with one or a combination of the components listed above as needed, into a suitable solvent, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and other necessary components from the components listed above. For sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying, which yield powders of the active ingredient and any additional desired components from its pre-sterilized filtered solution.

[0062] DPP-IV inhibitors or compositions comprising DPP-IV inhibitors may be formulated as tablets, hard or soft capsules, chewable 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 and lozenges, etc., may contain any of the following components or compounds of similar properties: binders, e.g., microcrystalline cellulose, tragacanth gum or gelatin; excipients, e.g., starch or lactose; disintegrants, e.g., alginic acid, Primogel or corn starch; lubricants, e.g., magnesium stearate or sterote; lubricants, e.g., colloidal silicon dioxide; sweeteners, e.g., sucrose or saccharin; or flavoring agents, e.g., peppermint, methyl salicylate or orange flavoring agents. Suitable tablets can be obtained, for example, by mixing at least one of the compounds that may be used in the present invention with known excipients, such as diluents, such as microcrystalline cellulose, calcium carbonate, calcium phosphate, or lactose; disintegrants, such as croscaramelose sodium, HPMC, sodium starch glycolate; binders, such as starch or gelatin, guar gum, or xanthan gum; lubricants, such as magnesium stearate or talc; and / or pharmaceuticals. The shapes include round, caplet, flat, elliptical, and chamfered edges, with or without embossing.

[0063] Capsules containing compounds that can be used in the present invention, such as hard or soft gelatin capsules, can be prepared, for example, by mixing the active compound with an inert carrier such as lactose or sorbitol and filling them into gelatin capsules. The capsules may or may not be imprinted.

[0064] Oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspension may also contain thickeners, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners and flavorings, as described above, can be added to provide an easily palatable oral preparation. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0065] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water are mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives to provide the active ingredient. Suitable dispersants or wetting agents and suspending agents are already exemplified above. Additional excipients, such as sweeteners, flavoring agents, and coloring agents, may also be present.

[0066] The composition may be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be naturally occurring gums, such as acacia gum or tragacanth gum, naturally occurring phosphatides, such as soy, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavorings.

[0067] Syrups and elixirs can be formulated with sweeteners, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain lubricants, preservatives, flavorings, and colorings.

[0068] Systemic administration may also be by mucosal or transdermal means. In the case of mucosal or transdermal administration, a suitable penetrating agent for the barrier to be penetrated can be used in the formulation. Such penetrating agents are commonly known in the art and include, for example, surfactants, bile salts, and fusidic acid derivatives in the case of mucosal administration. Mucosal administration can be achieved using nasal sprays or suppositories. The compound can be prepared in the form of suppositories for rectal delivery (e.g., using conventional suppository bases such as cocoa butter and other glycerides) or retained enemas.

[0069] The dosage of a DPP-IV inhibitor or a composition containing a DPP-IV inhibitor varies depending on the specific compound used, the metabolic stability and duration of action of the compound, the route and timing of administration, the rate of excretion, the duration of treatment, the severity of symptoms, the combination of drugs, the identity of any other therapeutic compounds administered, the subject, such as the age, weight, general health, sex, diet, size, and species of the human patient, and similar factors. Generally, the dosage of the DPP-IV inhibitor in this composition is the minimum effective dose to produce the desired effect with no or minimal side effects. The effective dose of the DPP-IV inhibitor may also be administered as two, three, four, five, six or more lower doses, administered separately at appropriate intervals throughout the day. Appropriate dose levels are generally about 10 to 250 mg / day and can be administered as single or multiple doses. Preferably, dose levels are about 0.5 to about 100 mg / kg / day. Appropriate dose levels may be approximately 0.01–250 mg / kg / day, approximately 0.05–100 mg / kg / day, or approximately 0.1–50 mg / kg / day. Within this range, doses may be 0.05–0.5, 0.5–5, or 5–50 mg / kg / day. For oral administration, the composition is preferably provided in the form of tablets containing 1.0–1000 milligrams of the 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 milligrams of the active ingredient, for symptomatic adjustment of the dose to the patient being treated. The compound may be administered in a regimen of 1 to 4 times daily, preferably once or twice daily. In one embodiment, the composition is administered to mice at a dose of 30 mg / kg / day to 70 mg / kg / day. In one embodiment, the composition is administered to D2.mdx mice at a dose of 50 mg / kg / day. In one embodiment, a broader human dose of the composition is 10 to 250 mg / day, administered in a single or multiple-dose regimen.

[0070] In one embodiment, a DPP-IV inhibitor or a composition comprising a DPP-IV inhibitor is used for the treatment or management of muscular dystrophy or both. Treatment or management includes inhibiting symptoms, i.e., halting the onset or progression of clinical symptoms, and / or alleviating symptoms, i.e., causing a regression of clinical symptoms. Compositions according to embodiments herein can be used to manage symptoms of muscular dystrophy, such as muscle weakness and wasting, and to slow the progression of the disease. Compositions can also be used to improve the quality of life of patients with dystrophy. In one embodiment, the composition provides a strategy for dystrophy-specific treatment that is applicable to virtually all patients, i.e., not limited to a limited subset of patients with mutation-specific muscular dystrophy.

[0071] In one embodiment, a DPP-IV inhibitor or a composition comprising a DPP-IV inhibitor upregulates eutrophin expression in muscle cells. Utrophin expression is regulated at multiple stages through its synthesis and degradation pathways. Various approaches to regulating eutrophin expression include, but are not limited to, direct mechanisms such as gene or protein substitution, as well as indirect mechanisms such as transcriptional upregulation, post-transcriptional regulation, and protein / mRNA stabilization of the eutrophin promoter. Utrophin can be upregulated by various signaling pathways, but are not limited to, AHR-ARNT, TGF-β, HDAC, GLP-1-PGC-1α, GABPα / β, and calcineurin-NFAT-mediated signaling pathways. In one embodiment, the composition upregulates eutrophin expression via inhibition of DPP-IV.

[0072] 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. DPP-IV inhibition can activate the PI3K / Akt signaling pathway in muscle cells, potentially increasing protein synthesis and muscle fiber size. Another mechanism by which the composition may exert its effect on muscular dystrophy is by stimulating mitochondrial biosynthesis. In one embodiment, the composition upregulates myogenic factors such as myogenin (MyoG) and MyoD. In one embodiment, the composition inhibits inflammation and muscle atrophy factors, thereby reducing muscle wasting. In one embodiment, the composition can reduce myofibrosis and muscle necrosis. In one embodiment, the composition has potential therapeutic effects in animal models and clinical trials and demonstrates its efficacy in humans.

[0073] There are several advantages to using DPP-IV inhibitors as off-label drugs for the upcontrol of eutrophin. DPP-IV inhibitors are potent, well-tolerated, orally bioavailable drugs with broad applicability, excellent safety and tolerability profiles, and are suitable for long-term use. DPP-IV inhibitors have also been proven safe for long-term use in pediatric (adolescent) and adult populations. DPP-IV inhibitors also exhibit anti-inflammatory and anti-fibrotic properties, along with the ability to prevent muscle wasting and myolysis, while simultaneously strengthening muscle fibers.

[0074] Embodiments of this specification also disclose a method for increasing utrophin expression in a subject requiring such effect, comprising administering to the subject a therapeutically effective dose 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.

[0075] Embodiments of this specification also disclose methods for treating muscular dystrophy. Methods according to embodiments of this specification involve 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. As used herein, the terms “effective” or “therapeutably effective” mean an amount of a compound that is nontoxic but present in an amount sufficient to provide the desired effect with a reasonable benefit / risk ratio for performing any medical treatment. The desired effect may be the alleviation of signs, symptoms or causes of the disease, or any other desired outcome in biological symptoms.

[0076] The subjects are generally male and female mammals, preferably human males or females, in which inhibition of dipeptidyl peptidase-IV enzyme activity is desired. In one embodiment, the subjects include mammals suffering from muscular dystrophy. In one embodiment, muscular dystrophy includes Fukuyama congenital muscular dystrophy (FCMD), myotonic muscular dystrophy, facioscapulohumeral muscular dystrophy (FSHD1 / 2), congenital muscular dystrophy (CMD1C), limb-girdle muscular dystrophy, Emery-Dreyfus muscular dystrophy (EDMD), myo-ophthalmoencephalopathy (MEB), Walker-Warburg syndrome (WWS), calpain opathies or LGMD2A, oculopharyngeal muscular dystrophy, Duchenne muscular dystrophy, Becker muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), Miyoshi muscular dystrophy type 1 (MMD1), and limb-girdle muscular dystrophy R2 dysferlin-associated (LGMDR2) muscular dystrophy.

[0077] The present invention is further illustrated by reference to the following examples, 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 many modifications to both materials and methods can be made without departing from the scope of the claimed embodiments.

[0078] Example 1 - In vitro upregulation of eutrophin with a DPP-IV inhibitor C2C12 myoblasts are seeded into well plates containing growth medium (10% FBS and DMEM). After the cells reach 70% confluence, they are added to differentiation medium (2% HS and DMEM) and differentiated for 7 days. Stock solutions are prepared by adding sitagliptin and other DPP-IV inhibitors, namely melogliptin, linagliptin, vildagliptin, and teneligliptin, in DMSO. Cells are treated with the final concentration 10 μM stock solution for 24 hours. RNA isolation is performed using the Qiagen assay kit and quantified using Nanodrop RT-PCR for eutrophin upcontrol.

[0079] Figure 1 shows the fold change in eutrophin levels at 10 μM concentrations for sitagliptin, melogliptin, linagliptin, vildagliptin, and teneligliptin. It is clear that all DPP-IV inhibitors can upregulate eutrophin levels in myoblasts.

[0080] Example 2 – Comparison of eutrophin upregulation by sitagliptin and ezthromide in vitro C2C12 myoblasts were treated with sitagliptin for 24 hours using the same protocol as in Example 1. Ezthromide is a known upregulator of eutrophin and was used as a positive control. RNA isolation and RT-PCR were performed to quantify the fold change in eutrophin mRNA expression. Figure 2 shows the fold change in eutrophin mRNA expression on C2C12 mouse skeletal muscle myoblasts with 10 μM sitagliptin compared to 10 μM ezthromide. Sitagliptin shows superior upregulation of eutrophin compared to ezthromide.

[0081] Example 3 – In vivo study of the D2.mdx mouse model Drug administration and efficacy evaluation protocol: All functional experimental parameters are evaluated in mdx-background wild-type mice and D2.mdx mice (D2.B10-DMD mdx / J mice (Strain#013141) from Jackson Laboratories, Bar Harbor, Maine (ME), USA 04609).

[0082] The test item involved orally administering sitagliptin 50 mg / kg once daily (qd) at a dose volume of 10 mL / kg (po). Sitagliptin suspended in a formulation containing 0.1% Tween20 and 0.5% carboxymethylcellulose (CMC) was administered orally once daily for 28 days. Wild-type and mdx control groups received only the vehicle (0.5% carboxymethylcellulose (CMC) containing 0.1% Tween20). The body weight of the research animals was recorded twice a week / twice daily before the study (before administration) and throughout the study. Animals were also monitored for clinical signs, mortality, and morbidity.

[0083] Experimental procedure and efficacy evaluation: D2.mdx mice and wild-type mice are trained for functional testing on a treadmill (Pan Lab, Harvard Instruments, USA) before baseline (day 0) performance is recorded on the treadmill for functional parameters of distance traveled and tolerance time. D2.mdx mice are randomized into the MDX-control group and the MDX-sitagliptin group based on their body weight and their treadmill functional parameters.

[0084] All three groups of mice (wild-type, DMD-control, and DMD-sitagliptin) underwent functional testing at week 0 (basic - day 0), week 2 (day 14), and end of the study (week 4 or day 28). Muscle function was assessed in response to vehicle and sitagliptin (50 mg / kg, oral) treatment by grip strength tests using a grip strength meter (Orchid Scientific, model: GSM02RS, India), hanging tests, treadmill running, and rotorod tests (Orchid Scientific, India). Blood samples were collected 30 minutes after the treadmill functional tests on days 0, 14, and 28 for creatine kinase (CK) analysis. The efficacy of sitagliptin was evaluated by comparing functional test parameters and serum CK levels of the treatment group with those of the mdx control group compared with baseline values ​​in the wild-type group.

[0085] Statistical analysis was performed using GraphPad Prism version 10 software, employing two-way ANOVA (multiple comparison method), followed by Tukey / Bonferroni "t" tests, with significance levels of ***p<0.001, **p<0.01, and *p<0.05 versus DMD-control (vehicle treatment) applied to the relevant locations on the drawing.

[0086] Figure 3 shows the protocol employed for the in vivo study of the D2.mdx mouse model. The D2.mdx mouse is a superior DMD model that reproduces several human features of DMD myopathology, such as lower hindlimb muscle weight, fewer muscle fibers, increased fibrosis and fat accumulation, as well as muscle weakness, compared to strains with this mutant allele in other genetic backgrounds. Six- and seven-week-old D2.mdx mice were selected for the 28-day in vivo study. Three cohorts of 10 animals each were selected: Group I, containing wild-type mice; Group II, containing D2.mdx control mice; and Group III (test item), containing sitagliptin-treated D2.mdx mice. Mice in all groups were subjected to training and randomization for 3 days (basostat, -3 days), followed by treatment for 28 days (0-28 days). Treadmill, grip strength, hanging, rotarod, and creatine kinase tests were recorded on days 0, 14, and 28. The treadmill experiment will be conducted using a mouse treadmill (Pan Lab, Harvard Instruments, USA). The rotarod test will be used as a parameter to record the overall improvement in muscle coordination.

[0087] Figure 4 shows the results of a treadmill test in D2.mdx mice, where Figure 4A shows the effect of sitagliptin on 30 minutes of travel distance according to the embodiments disclosed herein, and Figure 4B shows the effect of sitagliptin on tolerable time. The results suggest that sitagliptin shows significant and sustained improvements in travel distance and tolerable time over a 28-day treatment period.

[0088] Figures 5A and 5B show the effects of sitagliptin on normalized grip strength in D2.mdx mice before and after treadmill treatment, respectively, according to embodiments disclosed herein. Sitagliptin-treated mice were able to grip similarly to wild-type mice before treadmill stress. The hanging test also demonstrated that sitagliptin-treated mice functioned comparably to wild-type mice regardless of treadmill stress (Figures 6A and 6B). During the fall latency test in the rotarod test, sitagliptin-treated mice showed sustained improvement in overall muscle coordination (Figure 7).

[0089] Elevated serum creatinine kinase (CK) levels in blood samples indicate muscle breakdown caused by muscular dystrophy. Serum creatinine kinase levels were measured within 30 minutes after mice were subjected to a treadmill test. The pattern of creatinine kinase changes in mdx control mice follows published literature. Figure 8 shows that treatment with sitagliptin causes a significant decrease in serum creatinine kinase levels over 28 days of treatment.

[0090] Figures 9A–9F provide summaries of the 28-day study in the D2.mdx mouse model, including distance traveled, tolerance time, normalized grip strength before and after treadmill, and hanging tests before and after treadmill. Mice treated with sitagliptin showed robust improvements in all functional parameters compared to DMD disease control mice. Robust performance indicates an overall improvement in muscle function. These functional results suggest the potential utility of sitagliptin in the treatment of DMD.

[0091] The foregoing description of specific embodiments fully illustrates the general nature of the embodiments herein, so that others can readily modify and / or adapt such specific embodiments to various uses without departing from the general concept by applying their current knowledge, and such adaptations and modifications should and are intended to be understood within the meaning and scope of the equivalents of the disclosed embodiments. It should be understood that any expressions or terms used herein are for illustrative purposes only and not for limitation. Thus, although the embodiments herein have been described in terms of embodiments and examples, those skilled in the art will recognize that the embodiments and examples disclosed herein can be modified and implemented within the scope of the embodiments described herein.

Claims

1. A compound or a pharmaceutically acceptable salt thereof for preparing a medicament for the treatment or management of muscular dystrophy or both, wherein the compound is a DPP-IV inhibitor selected from the group consisting of sitagliptin, melogliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omaligliptin, evogliptin, gosogliptin, letagliptin, coflogliptin, fotagliptin, prusogliptin and combinations thereof.

2. The compound according to claim 1, wherein the compound is sitagliptin.

3. The compound according to claim 1, wherein the compound is sitagliptin phosphate monohydrate.

4. The compound according to claim 1, wherein the compound is melogliptin.

5. The compound according to claim 1, wherein the muscular dystrophy is selected from the group consisting of 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-Dreyfus muscular dystrophy (EDMD), myo-ophthalmoencephalopathy (MEB), Walker-Warburg syndrome (WWS), calpain opathies or LGMD2A, oculopharyngeal muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), Miyoshi muscular dystrophy type 1 (MMD1), and limb-girdle muscular dystrophy R2 dysferlin-associated (LGMDR2) muscular dystrophy.

6. The compound according to claim 1, wherein the compound is administered in combination with at least one additional 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.

7. The compound according to claim 6, wherein the corticosteroid therapy comprises the administration of at least one corticosteroid selected from the group consisting of prednisone, prednisolone, deflazacort, vamorolone, and combinations thereof.

8. The compound according to claim 6, wherein the exon skipping therapy comprises the administration of at least one agent selected from the group consisting of eteplirsen, golodylsen, ASO-based therapies, and combinations thereof.

9. The compound according to claim 6, wherein the epigenetic therapy comprises the administration of at least one agent selected from the group consisting of divinostat, Pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof.

10. The compound according to claim 1, wherein the dosage of the compound is in the range of 10 to 250 mg / day when administered in a single or multiple-dose regimen.

11. The compound according to claim 1, wherein the compound is formulated for intravenous, intramuscular, inhalation, intradermal, cutaneous, subcutaneous, oral, transdermal, transmucosal, topical, transnasal, transvaginal, intrathecal, epidural, transocular, or rectal administration.

12. A composition comprising the compound described in claim 1 or a pharmaceutically acceptable salt, solvate, or analog thereof, and optionally at least one pharmaceutically acceptable excipient.

13. The composition according to claim 12, wherein the compound is a DPP-IV inhibitor selected from the group consisting of sitagliptin, melogliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omaligliptin, evogliptin, gosogliptin, letagliptin, coflogliptin, fotagliptin, prusogliptin, and combinations thereof.

14. The composition according to claim 12, wherein the compound is sitagliptin.

15. The composition according to claim 12, wherein the compound is sitagliptin phosphate monohydrate.

16. The composition according to claim 12, wherein the pharmaceutically acceptable excipient is selected from the group consisting of mannitol, starch, xylitol, maltodextrin, hydroxypropyl methylcellulose, hydroxypropylcellulose, ethylcellulose, 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 calcium hydrogen phosphate, sodium stearyl fumarate, propyl gallate, poly(vinyl alcohol), macrogol 3350, titanium dioxide, red iron oxide and yellow iron oxide or mixtures thereof.

17. The composition according to claim 12, wherein the composition is administered in combination with at least one additional 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.

18. The composition according to claim 17, wherein the corticosteroid therapy comprises the administration of at least one corticosteroid selected from the group consisting of prednisone, prednisolone, deflazacort, vamorolone, and combinations thereof.

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

20. The composition according to claim 17, wherein the epigenetic therapy comprises the administration of at least one agent selected from the group consisting of divinostat, Pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof.

21. The composition according to claim 12, wherein the dosage of the composition is in the range of 10 to 250 mg / day when administered in a single or multiple dosing regimen.

22. The composition according to claim 12, wherein the composition is formulated for intravenous, intramuscular, inhalation, intradermal, cutaneous, subcutaneous, oral, transdermal, transmucosal, topical, transnasal, transvaginal, intrathecal, epidural, transocular, or rectal administration.

23. A method for treating muscular dystrophy, comprising administering a therapeutically effective amount of the compound described in claim 1 to a subject requiring treatment.

24. The method according to claim 23, wherein the compound is administered in combination with at least one additional 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.

25. The method according to claim 24, wherein the corticosteroid therapy comprises the administration of at least one corticosteroid selected from the group consisting of prednisone, prednisolone, deflazacort, vamorolone, and combinations thereof.

26. The method according to claim 24, wherein the exon skipping therapy comprises the administration of at least one agent selected from the group consisting of eteprirsen, golodylsen, ASO-based therapies, and combinations thereof.

27. The method according to claim 24, wherein the epigenetic therapy comprises administering at least one agent selected from the group consisting of divinostat, Pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof.

28. The method according to claim 23, wherein the muscular dystrophy is selected from the group consisting of 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-Dreyfus muscular dystrophy (EDMD), myo-ophthalmoencephalopathy (MEB), Walker-Warburg syndrome (WWS), calpain opathies or LGMD2A, oculopharyngeal muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), Miyoshi muscular dystrophy type 1 (MMD1), and limb-girdle muscular dystrophy R2 dysferlin-associated (LGMDR2) muscular dystrophy.

29. A method for upregulating eutrophin levels in muscle cells, comprising administering a therapeutically effective amount of the compound described in claim 1 to a target requiring such control.

30. The method according to claim 29, wherein the compound is administered in combination with at least one additional 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.

31. The method according to claim 30, wherein the corticosteroid therapy comprises the administration of at least one corticosteroid selected from the group consisting of prednisone, prednisolone, deflazacort, vamorolone, and combinations thereof.

32. The method according to claim 30, wherein the exon skipping therapy comprises administering at least one agent selected from the group consisting of eteprirsen, golodylsen, ASO-based therapies, and combinations thereof.

33. The method according to claim 30, wherein the epigenetic therapy comprises administering at least one agent selected from the group consisting of divinostat, Pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof.

34. Use of the compound according to 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 the group consisting of sitagliptin, melogliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omaligliptin, evogliptin, gosogliptin, letagliptin, coflogliptin, fotagliptin, prusogliptin, 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 the group consisting of 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-Dreyfus muscular dystrophy (EDMD), myo-ophthalmoencephalopathy (MEB), Walker-Warburg syndrome (WWS), calpain opathies or LGMD2A, oculopharyngeal muscular dystrophy, DMD-associated dilated cardiomyopathy (DCM), Miyoshi muscular dystrophy type 1 (MMD1), and limb-girdle muscular dystrophy R2 dysferlin-associated (LGMDR2) muscular dystrophy.

39. The use according to claim 34, wherein the compound is administered in combination with at least one additional 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.

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

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

42. The use according to claim 39, wherein the epigenetic therapy comprises the administration of at least one agent selected from the group consisting of divinostat, Pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof.

43. The use according to claim 34, wherein the dosage of the compound is in the range of 10 to 250 mg / day when administered in a single or multiple-dose 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 eutrophin levels in muscle cells.

46. The use according to claim 45, wherein the compound is a DPP-IV inhibitor selected from the group consisting of sitagliptin, melogliptin, linagliptin, vildagliptin, teneligliptin, saxagliptin, alogliptin, anagliptin, gemigliptin, trelagliptin, omaligliptin, evogliptin, gosogliptin, letagliptin, coflogliptin, fotagliptin, prusogliptin, 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 additional 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 according to claim 49, wherein the corticosteroid therapy comprises the administration of at least one corticosteroid selected from the group consisting of prednisone, prednisolone, deflazacort, vamorolone, and combinations thereof.

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

52. The use according to claim 49, wherein the epigenetic therapy comprises the administration of at least one agent selected from the group consisting of divinostat, Pan-HDAC inhibitors, HDAC6 inhibitors, and combinations thereof.

53. The use according to claim 45, wherein the dosage of the compound is in the range of 10 to 250 mg / day when administered in a single or multiple-dose 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.

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