Use of 5-HT4 receptor agonist for preventing, alleviating, or treating gastrointestinal motility disorders caused by GLP-1 receptor agonist

Abstract

The present invention relates to a use of a 5-HT4 receptor agonist for the purpose of preventing, alleviating, or treating gastrointestinal motility disorders caused by a GLP-1 receptor agonist and, more specifically, to the use of a medicament or composition containing a 5-HT4 receptor agonist for preventing, alleviating, or treating gastrointestinal motility disorders caused by a GLP-1 receptor agonist, by administering the medicament or composition simultaneously, substantially simultaneously, or sequentially, or according to another regimen, with a GLP-1 receptor agonist.

Description

Use for preventing, alleviating or treating gastrointestinal motility disorders induced by GLP-1 receptor agonists of 5-HT4 receptor agonists

[0001] The present invention relates to the use of a 5-HT4 receptor agonist for the purpose of preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, and more particularly, to the use of a medicament or composition comprising a 5-HT4 receptor agonist for the purpose of preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist by administering the medicament or composition simultaneously with the GLP-1 receptor agonist, substantially simultaneously with the GLP-1 receptor agonist, or sequentially, or on a different schedule.

[0002] Glucagon-like peptide-1 (GLP-1) receptor agonists are drugs that activate the GLP-1 receptor and are widely used to treat diabetes or obesity. A representative example is semaglutide (Ozempic), which is used to treat diabetes and obesity. ® for anti-diabetics, Wegovy ® for anti-obesity), liraglutide (Victoza ® for anti-diabetics), dulaglutide (Trulicity ® GLP-1 receptor agonists (GLP-1 receptor agonists) are currently being used as anti-diabetics. Based on the dementia prevention effect observed in large-scale real-world data (over 750,000 people) and clinical trials (over 15,000 people), and the cognitive function improvement effect observed in animal studies, GLP-1 receptor agonists are currently being tested as an Alzheimer's treatment. Therefore, the indications and market for GLP-1 receptor agonists are expected to expand significantly in the future.

[0003] Glucagon is a hormone secreted when blood sugar levels are low in the body. It regulates blood sugar levels by breaking down glycogen, a polysaccharide stored in the liver, into glucose, a monosaccharide. In addition to regulating blood sugar, it also suppresses digestive activity, promotes the release of fat from adipose tissue into the bloodstream, and suppresses appetite in the brain, acting on various organs. GLP-1 receptor agonists (GLP-1 receptor agonists) have similar effects to glucagon, and the most common side effects of GLP-1 receptor agonists are known to be digestive-related side effects such as indigestion, nausea, vomiting, abdominal bloating, and gastroesophageal reflux (excerpt from detailed information on Semaglutide). In fact, over 75% of diabetic patients have experienced indigestion, making it a common side effect that significantly impacts patients' quality of life. Common digestive enzymes do not significantly improve GLP-1 receptor agonist-induced gastric emptying. Treatment options include improving eating habits or reducing or changing the dosage of the GLP-1 receptor agonist that is causing the side effects. When treating with drug therapy, dopamine antagonists such as domperidone and itopride are used intermittently, but there are limitations such as using them as a second choice or only temporarily due to the side effects of the dopamine antagonists themselves.

[0004] The present invention provides a use of a 5-hydroxytryptamine receptor 4 (5-HT4 receptor) agonist for preventing, alleviating or treating gastrointestinal motility disorders induced by a glucagon-like peptide-1 (GLP-1) receptor agonist.

[0005] The present invention provides a medicament for preventing, alleviating or treating gastrointestinal motility disorders induced by GLP-1 receptor agonists, comprising a therapeutically effective amount of a 5-HT4 receptor agonist.

[0006] The present invention also provides a kit for preventing, alleviating or treating gastrointestinal motility disorders induced by a GLP-1 receptor agonist, comprising the following sets of (i) and (ii):

[0007] (i) a preparation containing a 5-HT4 receptor agonist, and

[0008] (ii) A formulation containing a GLP-1 receptor agonist.

[0009] The present invention also provides a method for preventing, alleviating, or treating gastrointestinal motility disorders induced by a GLP-1 receptor agonist, comprising administering a therapeutically effective amount of a 5-HT4 receptor agonist to a subject in need thereof.

[0010] The present invention also provides a use of a 5-HT4 receptor agonist for preventing, alleviating or treating gastrointestinal motility disorders induced by a GLP-1 receptor agonist.

[0011]

[0012] The present invention is described in detail below.

[0013]

[0014] According to one aspect of the present invention, a pharmaceutical composition is provided for preventing, alleviating or treating gastrointestinal motility disorders induced by a glucagon-like peptide-1 (GLP-1) receptor agonist comprising a therapeutically effective amount of a 5-hydroxytryptamine receptor 4 (5-HT4 receptor) agonist.

[0015]

[0016] According to one specific example of the present invention, the 5-HT4 receptor agonist may be, but is not limited to, mosapride, a pharmacologically active metabolite of mosapride, prucalopride, cisapride, tegaserod, naronapride, renzapride, PCS12852, or a piperidine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0017] [Chemical Formula 1]

[0018]

[0019]

[0020] In the above chemical formula 1,

[0021] A is phenyl or benzimidazole; wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy, and amino; wherein said benzimidazole may be optionally substituted with one or more substituents selected from the group consisting of halo, oxo (=O), amino, C1-C6 alkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl;

[0022] X is hydroxy or -OC(=O)NR1R2; wherein R1 and R2 are each independently -H, C1-C6 alkyl, benzyl, or a 5- to 7-membered carbocyclyl or heterocyclyl (which may be optionally substituted with one or more C1-C6 alkyl); or R1 and R2 together with the nitrogen atom to which they are attached may form a 5- to 7-membered heterocyclic ring;

[0023] B is phenyl, phenoxy, thienyl or naphthyl; wherein said phenyl, phenoxy, thienyl or naphthyl may be optionally substituted with one or more substituents selected from the group consisting of halo, nitro, cyano, methanesulfonyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, C1-C6 alkyl and C1-C6 alkoxy;

[0024] m is 1 or 2;

[0025] n is 0, 1, or 2.

[0026]

[0027] The piperidine compound of the above chemical formula 1 can be prepared by a person having ordinary knowledge of compound synthesis in the art using known compounds or compounds that can be easily prepared therefrom. In particular, a method for preparing the piperidine compound of the above chemical formula 1 is described in detail in International Publication No. WO 2010 / 044585 A2, U.S. Patent No. 8,642,772, etc., and the above documents are incorporated herein by reference. The piperidine compound of the above chemical formula 1 can be chemically synthesized by the method described in the above documents, but this is only to suggest one exemplary method, and the order of unit operations, etc. can be selectively changed as needed, and is not intended to limit the scope of the invention.

[0028]

[0029] According to another specific example of the present invention, in the chemical formula 1

[0030] A is phenyl; wherein said phenyl may be optionally substituted with one to three substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy and amino;

[0031] X is -OC(=O)NR1R2; wherein R1 and R2 are each independently -H, C1-C6 alkyl or benzyl;

[0032] B is phenyl; wherein said phenyl may be optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, C1-C6 alkyl and C1-C6 alkoxy;

[0033] m is 1 or 2;

[0034] n can be 0 or 1.

[0035] According to another specific example of the present invention, the piperidine compound of the above formula 1 may be (S)-(3-(4-(((4-amino-5-chloro-2-methoxybenzoyl)amino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl)carbamate ((S)-(3-(4-(((4-amino-5-chloro-2-methoxybenzoyl)amino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl)carbamate, relenopride) of the following formula 2:

[0036] [Chemical Formula 2]

[0037]

[0038]

[0039] According to another specific embodiment of the present invention, the agent for preventing, alleviating, or treating gastrointestinal motility disorders induced by the GLP-1 receptor agonist may additionally include a GLP-1 receptor agonist. Here, the GLP-1 receptor agonist refers to a drug having a GLP-1 receptor activating mechanism of action, including GLP-1, and includes GLP-1 / GIP (gastric inhibitory polypeptide) dual agonists, etc.

[0040] According to another specific embodiment of the present invention, the GLP-1 receptor agonist may be, but is not limited to, semaglutide, liraglutide, albiglutide, dulaglutide, exenatide, lixisenatide, retatrutide, orforglipron, tirzepatide, danuglipron, or CT-996.

[0041] In another embodiment of the present invention, the pharmaceutical composition may comprise a GLP-1 receptor agonist in an amount of 0.5 mg to 120 mg. In another embodiment of the present invention, the pharmaceutical composition may comprise semaglutide in an amount of 0.5 mg, 1 mg, 7 mg, or 14 mg. In another embodiment of the present invention, the pharmaceutical composition may comprise liraglutide in an amount of 1.2 mg or 1.8 mg. In another embodiment of the present invention, the pharmaceutical composition may comprise dulaglutide in an amount of 0.75 mg, 1.5 mg, 3 mg, or 4.5 mg. In another embodiment of the present invention, the pharmaceutical composition may comprise orforglipron in an amount of 12 mg, 24 mg, 36 mg, or 45 mg. According to another embodiment of the present invention, the drug may comprise danuglipron in an amount of 2.5 mg, 10 mg, 40 mg, 80 mg, or 120 mg taken twice daily.

[0042]

[0043] According to another aspect of the present invention, there is provided a kit-of-parts for preventing, alleviating or treating gastrointestinal motility disorders induced by a glucagon-like peptide-1 (GLP-1) receptor agonist, comprising the following sets of (i) and (ii):

[0044] (i) a preparation containing a 5-hydroxytryptamine receptor 4 (5-HT4 receptor) agonist, and

[0045] (ii) A formulation containing a GLP-1 receptor agonist.

[0046]

[0047] According to one specific example of the present invention, the 5-HT4 receptor agonist may be, but is not limited to, mosapride, a pharmacologically active metabolite of mosapride, prucalopride, cisapride, tegaserod, naronapride, renzapride, PCS12852, or a piperidine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

[0048]

[0049] [Chemical Formula 1]

[0050]

[0051]

[0052] In the above chemical formula 1,

[0053] A is phenyl or benzimidazole; wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy, and amino; wherein said benzimidazole may be optionally substituted with one or more substituents selected from the group consisting of halo, oxo (=O), amino, C1-C6 alkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl;

[0054] X is hydroxy or -OC(=O)NR1R2; wherein R1 and R2 are each independently -H, C1-C6 alkyl, benzyl, or a 5- to 7-membered carbocyclyl or heterocyclyl (which may be optionally substituted with one or more C1-C6 alkyl); or R1 and R2 together with the nitrogen atom to which they are attached may form a 5- to 7-membered heterocyclic ring;

[0055] B is phenyl, phenoxy, thienyl or naphthyl; wherein said phenyl, phenoxy, thienyl or naphthyl may be optionally substituted with one or more substituents selected from the group consisting of halo, nitro, cyano, methanesulfonyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, C1-C6 alkyl and C1-C6 alkoxy;

[0056] m is 1 or 2;

[0057] n is 0, 1, or 2.

[0058]

[0059] According to another specific example of the present invention, in the chemical formula 1

[0060] A is phenyl; wherein said phenyl may be optionally substituted with one to three substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy and amino;

[0061] X is -OC(=O)NR1R2; wherein R1 and R2 are each independently -H, C1-C6 alkyl or benzyl;

[0062] B is phenyl; wherein said phenyl may be optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, C1-C6 alkyl and C1-C6 alkoxy;

[0063] m is 1 or 2;

[0064] n can be 0 or 1.

[0065] According to another specific example of the present invention, the piperidine compound of the above chemical formula 1 may be (S)-(3-(4-(((4-amino-5-chloro-2-methoxybenzoyl)amino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl)carbamate ((S)-(3-(4-(((4-amino-5-chloro-2-methoxybenzoyl)amino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl)carbamate, relenopride) of the following chemical formula 2:

[0066] [Chemical Formula 2]

[0067]

[0068]

[0069] According to another embodiment of the present invention, the GLP-1 receptor agonist may be, but is not limited to, semaglutide, liraglutide, albiglutide, dulaglutide, exenatide, lixisenatide, retatrutide, orforglipron, tirzepatide, danuglipron, or CT-996.

[0070] According to another embodiment of the present invention, the kit may comprise a GLP-1 receptor agonist in an amount of 0.5 mg to 120 mg. According to another embodiment of the present invention, the kit may comprise semaglutide in an amount of 0.5 mg, 1 mg, 7 mg, or 14 mg. According to another embodiment of the present invention, the kit may comprise liraglutide in an amount of 1.2 mg or 1.8 mg. According to another embodiment of the present invention, the kit may comprise dulaglutide in an amount of 0.75 mg, 1.5 mg, 3 mg, or 4.5 mg. According to another embodiment of the present invention, the kit may comprise orforglipron in an amount of 12 mg, 24 mg, 36 mg, or 45 mg. According to another embodiment of the present invention, the kit may comprise danuglipron in an amount of 2.5 mg, 10 mg, 40 mg, 80 mg, or 120 mg taken twice daily.

[0071]

[0072] According to another embodiment of the present invention, the formulation of (i) and the formulation of (ii) may be administered simultaneously, substantially simultaneously or sequentially, or on different schedules.

[0073] According to another embodiment of the present invention, the kit may include, in addition to a formulation containing the active ingredient, a packaging container, instruction manual, and accompanying documents. The packaging container, instruction manual, and accompanying documents may describe combinations of substances for combined use. Furthermore, the form in which separate substances are administered together or as a mixture, as well as the dosage and administration, may be described.

[0074]

[0075] According to another specific embodiment of the present invention, the gastrointestinal motility disorder induced by the GLP-1 receptor agonist may be a digestive-related side effect due to gastrointestinal movement irregularity. According to another specific embodiment of the present invention, the digestive-related side effect due to the gastrointestinal movement irregularity may be, but is not limited to, indigestion, nausea, vomiting, abdominal distension, gastroesophageal reflux disease, gastroparesis, or constipation. The above-mentioned side effects of the GLP-1 receptor agonist can be prevented, alleviated, or treated by a 5-HT4 receptor agonist without affecting the weight loss efficacy of the GLP-1 receptor agonist, thereby improving the discomfort caused by the side effect and improving the quality of life.

[0076]

[0077] To measure the activity of 5-HT4 receptor agonists in alleviating the gastrointestinal motility disorder induced by GLP-1 receptor agonists, a GLP-1 receptor agonist-induced delayed gastric motor function model can be used. The GLP-1 receptor agonist-induced delayed gastric motor function model is an animal model of gastrointestinal motility disorder induced by administering a GLP-1 receptor agonist such as liraglutide to animals, and is used to discover drugs related to improving gastrointestinal motility disorder induced by GLP-1 receptor agonists (Diabetes, Obesity and Metabolism (2012) 14:531-538). Because the gastrointestinal motility disorders induced by GLP-1 receptor agonists in animals are clinically and histopathologically similar to those in humans, they can be used as useful animal models for drug discovery studies that alleviate gastrointestinal disorders induced by GLP-1 receptor agonists (Diabetes, Obesity and Metabolism (2012) 14:531-538; Journal of Diabetes and Its Complications (2014) 28:110-114).

[0078]

[0079] The 5-HT4 receptor agonist for preventing, alleviating or treating gastrointestinal motility disorders induced by the above GLP-1 receptor agonist can be administered orally or parenterally, alone or in combination with a conventional pharmaceutically acceptable carrier.

[0080]

[0081] According to another embodiment of the present invention, the medicament comprising the 5-HT4 receptor agonist or the preparation comprising the 5-HT4 receptor agonist can be used in the form of a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers. According to another embodiment of the present invention, the pharmaceutical composition can be administered in various dosage forms, for example, as solutions, suspensions, emulsions, microemulsions, multiple emulsions, forms, salves, pastes, plasters, ointments, tablets, coated tablets, rinses, capsules, for example, hard gelatin capsules and soft gelatin capsules, suppositories, rectal capsules, drops, gels, sprays, powders, aerosols, inhalants, eye drops, ophthalmic ointments, ophthalmic rinses, vaginal pessaries, vaginal rings, vaginal ointments, injections, infusion solutions and implants.

[0082] Applicable solid carriers may include one or more ingredients that may also function as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet disintegrants, or encapsulating materials. In the case of powders, the carrier may be a micronized solid mixed with the micronized active ingredient. In the case of tablets, the active ingredient is mixed with a carrier having the required compression properties in an appropriate proportion and compressed into the desired shape and size. Powders and tablets may contain up to 99% of the active ingredient.

[0083] Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes, and ion exchange resins. Liquid carriers can be used to prepare solutions, suspensions, emulsions, syrups, and elixirs.

[0084] The active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier, such as water, an organic solvent, a mixture thereof, or a pharmaceutically acceptable oil or fat. The liquid carrier may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, coloring agents, viscosity modifiers, stabilizers, or tonicity modifiers. Suitable examples of liquid carriers for oral and parenteral administration include water (especially those containing the above-mentioned additives, for example, cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (monohydric alcohols and polyhydric alcohols, for example, glycols) and their derivatives, and oils (for example, fractionated coconut oil and arachis oil).

[0085] Additionally, for parenteral administration, the carrier may be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions in the form of sterile liquids for parenteral administration. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be administered, for example, by intramuscular, intraperitoneal, or subcutaneous injection. Sterile solutions can also be administered intravenously. Parenteral administration can also be performed by subcutaneous, intramuscular, intraperitoneal, or intravenous injection using a syringe, optionally a pen-type syringe. Alternatively, parenteral administration can be performed using an infusion pump.

[0086] In another embodiment according to the present invention, the pharmaceutical composition can be applied to the formulation of controlled, sustained, delayed, delayed, and slow-release drug delivery systems. More specifically, the pharmaceutical composition can be applied to parenteral controlled-release and sustained-release systems, and more preferably, the controlled-release and sustained-release systems are administered subcutaneously. Without limiting the scope of the present invention, examples of useful controlled-release systems and compositions include hydrogels, oily gels, liquid crystals, polymeric micelles, microspheres, and nanoparticles. See generally Handbook of Pharmaceutical Controlled Release (Wise, DL, Marcel Dekker, New York, 2000) and Drug and the Pharmaceutical Sciences vol. 99: Protein Formulation and Delivery (MacNally, EJ, Marcel Dekker, New York, 2000).

[0087] Oral administration may be in the form of a liquid or solid composition. Preferably, the pharmaceutical composition may be in unit dosage form, such as a tablet, capsule, or suspension. In such form, the composition is subdivided into unit dosages containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged composition, such as a packaged powder, vial, ampoule, prefilled syringe, or sachet containing a liquid. Alternatively, the unit dosage form may be, for example, a capsule or tablet itself, or an appropriate number of any such composition in packaged form. The therapeutically effective dosage for use may be varied or adjusted by the administering physician and generally ranges from 1 mg to 1,000 mg, depending on the specific disease(s) to be treated and the patient's size, age, and response pattern.

[0088]

[0089] In the present invention, the dosage of the 5-HT4 receptor agonist will typically vary depending on the severity of the disease, the body weight of the subject being treated, and the metabolic state. A "therapeutically effective amount" for an individual patient means an amount sufficient to achieve the above-mentioned pharmacological effect, i.e., a therapeutic effect. In the present invention, the therapeutically effective amount of the 5-HT4 receptor agonist may be 1 to 1,000 mg, specifically 1 to 800 mg, 1 to 500 mg, 1 to 300 mg, 1 to 100 mg, 1 to 50 mg, or 1 to 30 mg, when administered to a human once daily.

[0090] However, the specific dosage used may vary depending on the patient's needs, the severity of the patient's condition, and the activity of the compound. Determining the optimal dosage in a given situation should be done clinically and is within the skill of the art.

[0091]

[0092] The terms "prevent", "preventing" and "prevention" as used herein mean reducing or eliminating the possibility of gastrointestinal motility disorders induced by GLP-1 agonists.

[0093] The terms "alleviate", "alleviating" and "alleviation" as used herein mean alleviating all or part of a disease and / or its accompanying symptoms.

[0094] The terms “treat,” “treating,” and “treatment” as used herein mean eliminating all or part of a disease and / or its accompanying symptoms.

[0095] The term "subject" as used herein means an animal, preferably a mammal (e.g., primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc.), and most preferably humans, that is the object of treatment, observation or experiment.

[0096] The term "composition" as used herein includes a product comprising a specified ingredient in a specified amount and any product resulting directly or indirectly from a combination of specified ingredients in specified amounts.

[0097] The drug and kit according to the present invention can effectively prevent, alleviate or treat gastrointestinal motility disorders induced by GLP-1 receptor agonists.

[0098] Figure 1 is a graph showing the results of measuring the effect of improving gastric emptying by single administration of mosapride, prucalopride, and relenopride of chemical formula 2 in a gastric motility inhibition model induced by liraglutide, a representative GLP-1 agonist.

[0099] Figure 2 is a graph showing the results of measuring the effect of improving gastric emptying by a single administration of mosapride and relenopride of chemical formula 2 in a gastric motility inhibition model induced by liraglutide, a representative GLP-1 agonist.

[0100] Figure 3 is a graph showing the results of measuring the effect of improving gastric emptying after administering mosapride, prucalopride, and relenopride of chemical formula 2 once daily for two weeks in a gastric motility inhibition model induced by liraglutide, a representative GLP-1 agonist.

[0101] Figure 4 is a graph showing the results of confirming the effects of mosapride, prucalopride, and relenopride of chemical formula 2 on the weight gain inhibition efficacy of liraglutide when mosapride, prucalopride, and relenopride of chemical formula 2 were administered once daily for two weeks in a gastric motility inhibition model induced by liraglutide, a representative GLP-1 agonist.

[0102] Hereinafter, the present invention will be described in more detail through examples. However, the following examples are provided merely to aid understanding of the present invention and are not intended to limit the scope of the present invention.

[0103]

[0104] laboratory animals

[0105] For this experiment, male Sprague-Dawley rats were purchased from Coretech Co., Ltd. in Korea and housed in polycarbonate rodent cages (W 235 x L 380 x H 175 mm) under an environment in which the temperature was 23±3℃, the relative humidity was 55±15%, and the light / dark cycle was automatically controlled with a 12-hour light / dark cycle, and food (food produced by Purina was purchased from Biopia) and water were freely available. They were stored and managed in accordance with the laboratory animal care standards of the Institutional Animal Care and Use Committee (IACUC). After a 7-day quarantine and acclimatization period after acquisition, 6-week-old rats were used in the experiment.

[0106]

[0107] Administration of test substances

[0108] Liraglutide was purchased from TOCRIS and dissolved in phosphate-buffered saline (PBS) vehicle containing 0.5% bovine serum albumin and administered intravenously (IV). Mosapride (mosapride citrate salt dehydrate) and prucalopride were purchased from Sigma chemical company and diluted in PBS vehicle containing 30% PEG400 and administered intraperitoneally (IP). Relenopride ((S)-(3-(4-(((4-amino-5-chloro-2-methoxybenzoyl)amino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl)carbamate) of chemical formula 2 was also diluted in PBS vehicle containing 30% PEG400 at each concentration and administered intraperitoneally (IP). Mosapride, prucalopride, or relenopride (Formula 2) was administered intraperitoneally to animals fasted for 24 h 60 minutes prior to the phenol red liquid meal. Liraglutide was administered intravenously (IV) 30 minutes after intraperitoneal administration of mosapride, prucalopride, or relenopride (Formula 2).

[0109]

[0110] Example 1: Effect of a single dose in a liraglutide-induced gastric motor dysfunction model.

[0111] The test compounds (relenopride, mosapride, and prucalopride of formula 2) for promoting gastrointestinal motility were injected intraperitoneally 60 minutes before administration of the phenol red meal, and liraglutide was administered 30 minutes after administration of the test compounds. Then, 2 mL of a liquid test meal labeled with phenol red was administered, and 20 minutes later, the animals were anesthetized and the stomachs were removed. Before removal, the esophagus and duodenum were tied to prevent the contents from leaking out. The control group was administered either vehicle only (denoted as “vehicle only”) instead of the test compounds and liraglutide, or vehicle and liraglutide (denoted as “vehicle”) instead of the test compounds. The analysis was conducted as follows.

[0112] 1. The separated stomach was placed in 0.1 N NaOH and ground with a homogenizer.

[0113] 2. Mix with 20% trichloroacetic acid and centrifuge at 2,500 xg.

[0114] 3. After mixing 2 mL of the supernatant with 2 mL of 0.5 N NaOH, the absorbance was measured at 560 nm.

[0115] 4. Gastric emptying rate (%) was calculated as described below.

[0116] Gastric emptying rate (%) = (1-OD of test stomach / OD of 0 time group stomach) × 100

[0117] Increase (%) = (GE% Test - GE% Vehicle) / GE% Vehicle × 100

[0118]

[0119] As can be seen in FIGS. 1 and 2, relenopride, mosapride, and prucalopride of chemical formula 2 showed significant gastrointestinal motility disorder alleviation effects at dosages of 1 to 10 mg / kg.

[0120] As is clear from the above experimental results, it was confirmed that mosapride, prucalopride and relenopride of chemical formula 2 have the activity of restoring gastrointestinal motility disorder caused by liraglutide, and thus are useful for treating gastrointestinal motility disorder caused by liraglutide.

[0121]

[0122] Example 2: Measurement of the effects on gastrointestinal motility disorder and body weight after two weeks of repeated administration in a liraglutide-induced gastric motor dysfunction model.

[0123] The effects of mosapride, prucalopride, and relenopride and liraglutide of chemical formula 2 on gastrointestinal motility disorders and body weight were investigated after repeated daily administration for two weeks.

[0124] As can be seen in Figure 3, mosapride, prucalopride, and relenopride of chemical formula 2 all showed significant gastrointestinal motility disorder relief effects at a dose of 10 mg / kg.

[0125] In addition, as can be seen in Fig. 4, neither mosapride, prucalopride, nor relenopride of chemical formula 2 affected the weight gain inhibition effect of liraglutide.

[0126] As is clear from the above experimental results, it was confirmed that mosapride, prucalopride, and relenopride of chemical formula 2 have the activity of restoring gastrointestinal motility disorder caused by liraglutide, and do not affect the weight loss efficacy of liraglutide.

[0127]

[0128] Statistical analysis

[0129] All data are presented as mean ± standard deviation. The results of this experiment were analyzed using parametric multiple comparison procedures, assuming data normality.

[0130] If the parametric one-way ANOVA results were significant, a post-hoc test was conducted using Dunnett's multiple comparison test.

[0131] Statistical analysis was performed using Prism 7.04 (GraphPad Software Inc., San Diego, CA, USA), and a p value less than 0.05 was considered statistically significant.

[0132] Statistical significance was expressed as *p<0.05, **p<0.01, ***p<0.001.

Claims

1. A drug for preventing, alleviating or treating gastrointestinal motility disorders induced by a glucagon-like peptide-1 (GLP-1) receptor agonist containing a therapeutically effective amount of a 5-hydroxytryptamine receptor 4 (5-HT4 receptor) agonist.

2. A drug for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the 5-HT4 receptor agonist in paragraph 1 is mosapride, a pharmacologically active metabolite of mosapride, prucalopride, cisapride, tegaserod, naronapride, renzapride, PCS12852 or a piperidine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof: [Chemical Formula 1] In the above chemical formula 1, A is phenyl or benzimidazole; wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy, and amino; wherein said benzimidazole may be optionally substituted with one or more substituents selected from the group consisting of halo, oxo (=O), amino, C1-C6 alkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl; X is hydroxy or -OC(=O)NR1R2; wherein R1 and R2 are each independently -H, C1-C6 alkyl, benzyl, or a 5- to 7-membered carbocyclyl or heterocyclyl (which may be optionally substituted with one or more C1-C6 alkyl); or R1 and R2 together with the nitrogen atom to which they are attached may form a 5- to 7-membered heterocyclic ring; B is phenyl, phenoxy, thienyl or naphthyl; wherein said phenyl, phenoxy, thienyl or naphthyl may be optionally substituted with one or more substituents selected from the group consisting of halo, nitro, cyano, methanesulfonyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, C1-C6 alkyl and C1-C6 alkoxy; m is 1 or 2; n is 0, 1, or 2.

3. In paragraph 2, A is phenyl; wherein said phenyl may be optionally substituted with one to three substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy and amino; X is -OC(=O)NR1R2; wherein R1 and R2 are each independently -H, C1-C6 alkyl or benzyl; B is phenyl; wherein said phenyl may be optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, C1-C6 alkyl and C1-C6 alkoxy; m is 1 or 2; A drug for preventing, alleviating or treating gastrointestinal motility disorders induced by a GLP-1 receptor agonist, wherein n is 0 or 1.

4. A drug for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the piperidine compound of the chemical formula 1 in the second paragraph is (S)-(3-(4-(((4-amino-5-chloro-2-methoxybenzoyl)amino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl)carbamate of the following chemical formula 2: [Chemical Formula 2] 5. A drug for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that it comprises the piperidine compound of the chemical formula 1 in an amount of 1 mg to 1,000 mg in the second paragraph.

6. A drug for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that it further comprises a GLP-1 receptor agonist according to any one of claims 1 to 5.

7. A drug for preventing, alleviating, or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the GLP-1 receptor agonist in paragraph 6 is semaglutide, liraglutide, albiglutide, dulaglutide, exenatide, lixisenatide, retatrutide, orforglipron, tirzepatide, danuglipron, or CT-996.

8. A drug for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that it comprises the GLP-1 receptor agonist in an amount of 0.5 mg to 120 mg in accordance with claim 6.

9. A drug for preventing, alleviating, or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the gastrointestinal motility disorder induced by the GLP-1 receptor agonist according to any one of claims 1 to 5 is a digestive-related side effect caused by gastrointestinal movement irregularity.

10. A drug for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the digestive-related side effects caused by the irregularity of the gastrointestinal motility in claim 9 are indigestion, nausea, vomiting, abdominal distension, gastroesophageal reflux disease, gastroparesis or constipation.

11. A kit (kit-of-parts) for preventing, alleviating or treating gastrointestinal motility disorders induced by a glucagon-like peptide-1 (GLP-1) receptor agonist comprising the following sets of (i) and (ii): (i) a preparation containing a 5-hydroxytryptamine receptor 4 (5-HT4 receptor) agonist, and (ii) A formulation containing a GLP-1 receptor agonist.

12. A kit for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the 5-HT4 receptor agonist in claim 11 is mosapride, a pharmacologically active metabolite of mosapride, prucalopride, cisapride, tegaserod, naronapride, renzapride, PCS12852 or a piperidine compound of the following chemical formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof: [Chemical Formula 1] In the above chemical formula 1, A is phenyl or benzimidazole; wherein said phenyl may be optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy, and amino; wherein said benzimidazole may be optionally substituted with one or more substituents selected from the group consisting of halo, oxo (=O), amino, C1-C6 alkyl, C1-C6 alkoxy, and C3-C7 cycloalkyl; X is hydroxy or -OC(=O)NR1R2; wherein R1 and R2 are each independently -H, C1-C6 alkyl, benzyl, or a 5- to 7-membered carbocyclyl or heterocyclyl (which may be optionally substituted with one or more C1-C6 alkyl); or R1 and R2 together with the nitrogen atom to which they are attached may form a 5- to 7-membered heterocyclic ring; B is phenyl, phenoxy, thienyl or naphthyl; wherein said phenyl, phenoxy, thienyl or naphthyl may be optionally substituted with one or more substituents selected from the group consisting of halo, nitro, cyano, methanesulfonyl, trifluoromethyl, trifluoromethoxy, difluoromethoxy, phenyl, C1-C6 alkyl and C1-C6 alkoxy; m is 1 or 2; n is 0, 1, or 2.

13. In paragraph 12, A is phenyl; wherein said phenyl may be optionally substituted with one to three substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy and amino; X is -OC(=O)NR1R2; wherein R1 and R2 are each independently -H, C1-C6 alkyl or benzyl; B is phenyl; wherein said phenyl may be optionally substituted with one to three substituents selected from the group consisting of halo, nitro, cyano, C1-C6 alkyl and C1-C6 alkoxy; m is 1 or 2; A kit for preventing, alleviating or treating gastrointestinal motility disorders induced by a GLP-1 receptor agonist, wherein n is 0 or 1.

14. A kit for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the piperidine compound of the chemical formula 1 in the 12th paragraph is (S)-(3-(4-(((4-amino-5-chloro-2-methoxybenzoyl)amino)methyl)piperidin-1-yl)-1-(4-fluorophenyl)propyl)carbamate of the following chemical formula 2: [Chemical Formula 2] 15. A kit for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that it comprises the piperidine compound of the chemical formula 1 in an amount of 1 mg to 1,000 mg in accordance with claim 12.

16. A kit for preventing, alleviating, or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the GLP-1 receptor agonist is semaglutide, liraglutide, albiglutide, dulaglutide, exenatide, lixisenatide, retatrutide, orforglipron, tirzepatide, danuglipron, or CT-996, according to any one of claims 11 to 15.

17. A kit for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that it comprises the GLP-1 receptor agonist in an amount of 0.5 mg to 120 mg according to any one of claims 11 to 15.

18. A kit for preventing, alleviating, or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the gastrointestinal motility disorder induced by the GLP-1 receptor agonist according to any one of claims 11 to 15 is a digestive-related side effect caused by gastrointestinal movement irregularity.

19. A kit for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the digestive-related side effects caused by the irregularity of the gastrointestinal motility in claim 18 are indigestion, nausea, vomiting, abdominal distension, gastroesophageal reflux disease, gastroparesis or constipation.

20. A kit for preventing, alleviating or treating gastrointestinal motility disorder induced by a GLP-1 receptor agonist, characterized in that the preparation of (i) and the preparation of (ii) are administered simultaneously, substantially simultaneously or sequentially, or on a different schedule, according to any one of the preceding claims 11 to 15.

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