SGLT1 selective inhibitor and pharmaceutical applications thereof

Abstract

[Problem] To provide a pharmaceutical drug or the like that is useful for preventing or treating respiratory diseases such as cystic fibrosis in which mucociliary clearance is impaired. [Solution] The present invention relates to a pharmaceutical drug that is useful for preventing or treating a respiratory disease such as cystic fibrosis in which mucociliary clearance is impaired, the pharmaceutical drug comprising, as an active ingredient, the SGLT1 selective inhibitor 3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide or a pharmacologically acceptable salt thereof. The pharmaceutical drug according to the present invention inhibits the absorption of glucose and water from the lumen of the lungs, suppresses lumen moisture clearance of the lungs, improves airway mucus hydration and mucociliary clearance, and is useful for the prevention or treatment of respiratory diseases such as cystic fibrosis in which mucociliary clearance is impaired.

Description

SGLT1 Selective Inhibitor and Its Pharmaceutical Use

[0001] The present invention relates to a pharmaceutical useful for the prevention or treatment of respiratory diseases such as cystic fibrosis having a disorder in mucociliary transport clearance.

[0002] More specifically, the present invention relates to a formula: An SGLT1 selective inhibitor represented by (chemical name: 3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazol-4-ylmethyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide; hereinafter, may be abbreviated as "Compound 1") or a pharmaceutically acceptable salt thereof as an active ingredient, and is useful for the prevention or treatment of respiratory diseases such as cystic fibrosis having a disorder in mucociliary transport clearance.

[0003] The lung has a biological defense system that minimizes the possibility of airway infection and colonization, and the mucociliary transport system plays an important role. However, when abnormalities occur in the mucociliary transport system such as an increase in airway secretion, an abnormality in the composition of airway mucus, or difficulty in excretion, it causes daily life disorders, promotes airway infection, and ventilation disorders. Respiratory diseases with disorders in mucociliary transport clearance include cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis (including non-cystic fibrosis bronchiectasis), chronic airway infections, diffuse panbronchiolitis, paranasal bronchial syndrome, bronchial asthma, and primary ciliary dyskinesia, etc. have been reported. (Kondo Mitsuko, Tamaki Jun, Japanese Journal of Internal Medicine, 2012, 101(12), p. 3525-3532) The treatment of the respiratory symptoms of these diseases is based on promoting the excretion of sputum by a combination of drugs that improve mucociliary transport clearance such as respiratory physiotherapy, expectorants, and bronchodilators, and early diagnosis of respiratory infections and using appropriate antibacterial drugs.

[0004] In cystic fibrosis, abnormalities in ion transport reduce the water content of airway mucus, leading to decreased mucociliary transport clearance. As a result, the proportion of solid components in the mucus gel increases, causing the accumulation of highly viscous mucus, leading to recurrent bronchiolitis and bronchitis, and symptoms such as expectoration of purulent sputum, cough, and dyspnea (Jun Tamaki, Japanese Journal of Respiratory Medicine, 1998, 36(3), pp. 217-223). Dornase alfa breaks down DNA in purulent mucus in the airways, facilitating sputum expulsion, while inhalation of hypertonic saline (6-7%) or inhaled mannitol (bronchitol) improves mucus clearance, making it easier to expel sputum.

[0005] Mucus gel hydration is crucial for mucociliary transport clearance. Mucus hydration is regulated by the coordinated action of several ion channels and transporters. In cystic fibrosis, impaired function of cystic fibrosis transmembrane conduction regulator (CFTR) impairs chloride and water transport, leading to decreased airway mucus hydration and reduced mucociliary transport clearance. In addition to CFTR, factors involved in water transport include calcium-dependent chlorine conductance (CaCC; TMEM16A), epithelial sodium channels (ENaC), aquaporins, facilitative glucose transporters (GLUTs), and sodium-coupled glucose cotransporters (SGLTs) (Misbahuddin M Rafeeq and Hissam Aly Sayed Murad, J Transl Med, 2017, 15(84), DOI 10.1186 / s12967-017-1193-9; Deborah L Baines et al., Am J Physiol Cell Physiol, 2023, 324(1), C153-C166). Various approaches are being attempted to develop new treatment options.

[0006] As one approach to controlling water transport from the airway lumen to the basement membrane, aiming to improve airway mucus hydration and mucociliary transport clearance, ENaC inhibitors, which control sodium ion influx, are attracting attention. ENaC, present in the airway lumen, works in conjunction with Na+ / K+-ATPase, present in the basement membrane, to pump sodium ions from the airway lumen to the basement membrane. The resulting osmotic pressure difference also causes water to move from the airway lumen to the basement membrane. Therefore, ENaC inhibitors such as Amiloride, AZD5634, and SPX-101, and Na+ / K+-ATPase inhibitors such as Ouabain, suppress the movement of sodium ions from the airway lumen to the basement membrane, and also suppress the movement of water, thereby increasing the hydration of airway mucus and improving mucociliary transport clearance (Atsujiro Uchida, Artificial Respiration, 2004, 21, 1, pp. 21-28; Moore PJ, Tarran R, Expert Opin Ther Targets, 2018, 22, pp. 687-701). There are high expectations for ENaC inhibitors as therapeutic agents, and research and development is progressing on many drugs, but ENaC inhibitors also have pharmacodynamic and pharmacokinetic challenges and have not yet reached the stage of becoming therapeutic agents (Peter Nickolaus, ERJ Open Res, 2020, 6, 00429-2020). New options for improving mucociliary transport clearance are needed.

[0007] In addition to ENaC, glucose transporters are also thought to be involved in the absorption of water from the luminal side of the lung, which is important for mucociliary transport clearance. Water moves along with glucose during the facilitated diffusion transport by GLUTs. Furthermore, some studies suggest the involvement of SGLT1 using phlorizin (1 mM), a nonspecific inhibitor of glucose transporters, and SGLT1 / SGLT2 inhibitors (Satoshi Suzuki et al., Japanese Journal of Chest Disease, 1996, 34(10), pp. 1109-1114; Hiroyuki Hirai et al., Molecular Therapy: Methods & Clinical Development, 2022, 24, pp. 11-19). However, considering that phlorizin is also an inhibitor of Na+ / K+-ATPase, and that its degradation product, phloretin, also inhibits GLUT1 (Ehrenkranz JRL et al., Diabetes Metab Res Rev, 2005, 21(1), pp. 31-38), these studies do not clearly demonstrate the significant involvement of SGLT1. Conversely, some reports suggest that increasing SGLT1 activity is effective in treating cystic fibrosis, while SGLT1 inhibitors worsen the condition. Therefore, no clear conclusion has been reached regarding the involvement of SGLT1 (Tales L Oliveira et al., Scientific Reports, 2016, 6, 21752, DOI:10.1038 / srep21752).

[0008] The SGLT1 molecule focused on in this invention transports one molecule of glucose and water in conjunction with two sodium ions, acting as both a glucose and water transporter, and is present in the small intestine, kidneys, lungs, liver, etc. (Wright EM et al., Physiology, 2004, 19, pp. 370-376; Masayuki Isaji, Genetic Medicine MOOK 19, 2011, pp. 170-175). In fact, appropriate amounts of sodium ions and glucose are added to hydration solutions used in cases of dehydration to efficiently transport water via SGLT1 in the small intestine. The function and role of SGLT1 in the small intestine and kidneys are being elucidated, and there is ample evidence from preclinical and clinical trials showing that compound 1 is useful in treating diabetes and constipation. On the other hand, although the localization of SGLT1 in lung airway epithelial cells and alveolar epithelial cells (Deborah L Baines et al., Am J Physiol Cell Physiol, 2023, 324(1), C153-C166) and other tissues such as the liver has been reported, its pathophysiological significance has not been fully elucidated.

[0009] Compound 1 was discovered as a selective inhibitor of SGLT1. While phlorizin has a Ki value of 201 nM for human SGLT1, compound 1 has a Ki value of 27 nM for human SGLT1, indicating strong inhibitory activity. Furthermore, while phlorizin is non-selective (0.13 times) and shows higher selectivity for SGLT2, compound 1 exhibits a high selectivity of 303 times for SGLT1 (Non-Patent Document 1). It is known that when administered orally, it selectively acts on SGLT1 present in the gastrointestinal lumen, suppressing sugar absorption from the small intestine and correcting hyperglycemia in diabetes (Patent Documents 1 and 2). It is also known to be useful as a treatment for constipation by improving stool consistency (Patent Document 3, Non-Patent Documents 1 and 2). In recent years, clinical development has also progressed on its use as a treatment for post-gastrectomy hypoglycemia (PBH) by suppressing rapid sugar absorption (Patent Document 4).

[0010] However, it is not known that SGLT1 selective inhibitors, including compound 1 or its pharmacologically acceptable salts (such as KGA-2727, JTT-662, and LX2761), control glucose absorption in the pulmonary lumen, thereby suppressing water absorption and inhibiting water clearance in the pulmonary lumen, thereby improving airway mucus hydration and mucociliary transport clearance. Furthermore, it is not known that these inhibitors are useful as preventative or therapeutic agents for respiratory diseases such as cystic fibrosis, which are characterized by impaired mucociliary transport clearance.

[0011] Japanese Patent Publication No. 4597048, Japanese Patent Publication No. 5144683, Japanese Unexamined Patent Publication No. 2015-83580, WO2019 / 191352 A1

[0012] Inoue T et al., Eur J Pharmacol, 2017, 806, p. 25-31 Fukudo S et al., Lancet Gastroenterol Hepatol, 2018, 3(9), p. 603-613

[0013] The present invention aims to provide pharmaceuticals or other products useful for the prevention or treatment of respiratory diseases such as cystic fibrosis, which are characterized by impaired mucociliary transport clearance.

[0014] The present invention relates to a pharmaceutical product for the prevention or treatment of respiratory diseases such as cystic fibrosis, which are characterized by impaired mucociliary transport clearance, comprising compound 1, which is a selective SGLT1 inhibitor, or a pharmaceutically acceptable salt thereof, as an active ingredient.

[0015] In other words, the present invention relates to: [1] a pharmaceutical product for the prevention or treatment of respiratory diseases involving impaired mucociliary transport clearance, comprising an SGLT1 selective inhibitor as an active ingredient; [2] the pharmaceutical product according to [1], wherein the SGLT1 selective inhibitor comprises 3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole-4-ylmethyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide or a pharmaceutically acceptable salt thereof as an active ingredient; [3] the pharmaceutical product according to [2], wherein the salt comprises bis[3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole-4-ylmethyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide] monosebacate (Mizagliflozin) as an active ingredient; [4] The present invention relates to any of the pharmaceuticals described in [1], [2], or [3] above, wherein the respiratory disease in which mucociliary transport clearance is impaired is at least one disease selected from the group consisting of cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis (including non-cystic fibrotic bronchiectasis), chronic respiratory tract infection, diffuse panbronchiolitis, sinobronchial syndrome, bronchial asthma, and primary ciliary dysfunction.

[0016] The pharmaceutical product of the present invention has the effect of suppressing water clearance from the pulmonary lumen, hydrating mucus gels, and improving mucociliary transport clearance, and is useful for the prevention or treatment of respiratory diseases such as cystic fibrosis, which are impaired mucociliary transport clearance.

[0017] Compound 1 of the present invention may be used after being converted to a prodrug as appropriate. For example, a prodrug of compound 1 can be produced by introducing groups constituting the prodrug to one or more arbitrary groups selected from the hydroxyl group, amino group, and amino group on the pyrazole ring of compound 1 using a prodrug formulation reagent such as a corresponding halide, in accordance with a conventional method, and then, if desired, by isolating and purifying in accordance with a conventional method (see, for example, Japanese Patent Publication No. 6-298790, Japanese Patent Publication No. 8-27006, Journal of Molecular Catalysis B: Enzymatic 27, 2004, pp. 1-6, etc.). As groups constituting the prodrug, for example, groups described in "Development of Pharmaceuticals" (Hirokawa Shoten, 1990, 7, pp. 163-198) can be used. Specifically, when introducing a group that constitutes a prodrug to the 6th position (such as a hydroxyl group) of a sugar, examples include a lower acyl group, a lower alkoxy (lower acyl) group (meaning a lower acyl group substituted with a lower alkoxy group; the same applies hereinafter), a lower alkoxycarbonyl (lower acyl) group, a lower alkoxycarbonyl group, an aryl (lower alkoxycarbonyl) group, a lower alkoxy (lower alkoxycarbonyl) group, etc. Note that "lower" in the context of "lower alkyl" or "lower alkoxy" means a linear or branched group with 1 to 6 carbon atoms, and in the context of "lower acyl" or "lower alkoxycarbonyl," it means a linear or branched group with 2 to 7 carbon atoms. The term "aryl" refers to a 1-3 cyclic aromatic hydrocarbon group such as a phenyl group or a naphthyl group. Examples of prodrugs aimed at lung selectivity include lung-targeted drug delivery systems, lung surfactant mimicry, lung-specific enzymes, alveolar macrophages, and nanoparticle drug delivery.

[0018] In the present invention, compound 1 and its prodrug can be prepared as pharmaceutically acceptable salts by conventional methods. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, nitric acid, and phosphoric acid; acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, benzoic acid, sebacic acid, and pamoic acid; and salts with inorganic bases, organic bases, or basic amino acids. Furthermore, pharmaceutically acceptable salts of compound 1 or its prodrug also include solvates with pharmaceutically acceptable solvents (e.g., water, ethanol, etc.). More preferably, monosebacate of compound 1, half fumarate of compound 1, etc.

[0019] Compound 1 is typically administered as part of a pharmaceutical composition. Therefore, the present invention further provides a pharmaceutical composition containing Compound 1 together with pharmaceutically acceptable additives.

[0020] The pharmaceutical product of the present invention can be formulated for bronchial (inhalation), oral, rectal, intranasal, topical (including skin, transdermal, ophthalmic, oral, and sublingual), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration, and can be prepared by any method in the field of pharmacy. Bronchial (inhalation) formulations are preferred.

[0021] The pharmaceuticals of the present invention can be manufactured in various dosage forms by conventional methods by appropriately mixing or diluting / dissolving the active ingredient with a pharmaceutical carrier such as an appropriate excipient, disintegrant, binder, lubricant, flow promoter, diluent, bulking agent, granulator, coating agent, solvent, auxiliary solvent, suspending agent, buffer, isotonic agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, solubilizer, sweetener, fragrance, odor masking agent, colorant, caking inhibitor, humectant, chelating agent, plasticizer, thickener, antioxidant, surfactant, and buffer.

[0022] The selection of appropriate pharmaceutically acceptable excipients is described, and useful resources exist for the selection of appropriate pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Science (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and the Pharmaceutical Press).

[0023] The pharmaceuticals of the present invention can be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamidophenol, polyhydroxyethyl aspartamidophenol, or polyethylene oxide polylysine substituted with palmitoyl residues. Furthermore, the pharmaceuticals of the present invention can be coupled with certain biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and hydrogels of crosslinked or amphiphilic block copolymers.

[0024] Inhalation administration to the lungs can be achieved by the use of a suitable aerosol propellant (including the pharmaceutically acceptable The aerosol formulation is packaged in a canister, and the appropriate dose is delivered by a dispensing valve (e.g., supplied by Bespak, Valois, or 3M, or by Aptar, Coster, or Vari).

[0025] Inhalation administration to the lungs can also be achieved by using non-pressurized formulations such as aqueous solutions or suspensions. These can be administered by nebulizers, such as handheld and portable nebulizers, or by home or hospital (non-portable) nebulizers. The formulations may contain water, buffers, isotonic modifiers, pH modifiers, surfactants, and additives such as cosolvents. Suspensions and aerosol formulations (whether pressurized or non-pressurized) typically contain the pharmaceutical product of the present invention in a finely ground form having a D50 of, for example, 0.5 to 10 μm, or about 1 to 5 μm. The particle size distribution can be expressed using D10, D50, and D90 values. The median D50 of the particle size distribution is defined as the particle size in microns that divides the distribution in half.

[0026] Dry powder compositions for local delivery to the lungs by inhalation may be provided, for example, in capsules and cartridges, such as gelatin capsules and cartridges, or in blister packs, such as laminated aluminum boxes, for use in inhalers or insufflers. Powder mixture formulations typically contain the pharmaceutical of the present invention and an inhalation powder mixture of a suitable powder base (carrier / diluent / excipient), such as a monosaccharide, disaccharide, or polysaccharide (e.g., lactose or starch). Each capsule or cartridge may typically contain 0.02 mg to 160 mg of the pharmaceutical composition, optionally in combination with other active ingredients. Alternatively, the pharmaceutical of the present invention may be provided without excipients.

[0027] Preferably, the packing / medication dispenser is of a type selected from the group consisting of reservoir dry powder inhalers (RDPIs), multi-dose dry powder inhalers (MDPIs), and metered-dose inhalers (MDIs).

[0028] The pharmaceutical product of the present invention can be administered in combination with other drugs used for the prevention or treatment of respiratory diseases and symptoms such as cystic fibrosis.

[0029] Suitable additional activators included in pharmaceutical compositions or combination preparations of the pharmaceutical product of the present invention containing compound 1 as an active ingredient include: β2 adrenergic receptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, indacaterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol, orodaterol, vilanterol, and avesiderol; and antihistamine H1 receptor antagonists such as loratadine, cetirizine, desloratadine, levocetirizine, fexofenadine, astemizole, azelastine, and chlorpheniramine. or H4 receptor antagonists; corticosteroids such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, pecrometasone dipropionate, budesonide, fluticasone propionate, mometasone furoate, and fluticasone furoate; leukotriene antagonists such as montelukast and zafirlukast; anticholinergic compounds such as ipratropium, tiotropium, glycopyrrolate, acridinium, and umeclidinium (especially muscarinic antagonists) CFTR repair therapies such as Ibacaftol, QBW251, Bamacaftol (VX659), Elexacaftol (VX445), VX561 / CPT-656, VX152, Oracaftol (VX440), GLP2737, GLP2222, GLP2451, PTI438, PTI801, PTI808, FDL-176 (e.g., CFTR enhancers, correctors or amplifiers), as well as CFTR correctors such as Lumacaftol and Tezacaftol, or combinations thereof such as Orcavy and Tricafta; Amyloride, Examples include ENaC modulators (especially ENaC inhibitors) such as VX-371, AZD5634, QBW276, SPX-101, BI443651, BI1265162, and ETD001; CNP-146a; dorunase alfa; antibiotics; antiviral agents such as ribavirin and neuraminidase inhibitors such as zanabimir; antifungal agents such as PUR1900; respiratory tract hydration agents (osmotic pressure modifiers) such as hypertonic saline and mannitol (bronchitol®); and mucolytic agents such as N-acetylcysteine.When the pharmaceutical product of the present invention is used in combination with the above-mentioned drugs, the present invention includes any of the following forms: simultaneous administration as a single formulation, simultaneous administration via the same or different routes of administration as separate formulations, and staggered administration via the same or different routes of administration as separate formulations.

[0030] The dosage and frequency of administration of the active ingredient of the present invention may be appropriately determined according to the patient's weight, age, sex, and the severity of the disease. When administered by inhalation, for example, the daily dose may be 0.02 mg to 160 mg / day, divided into one to ten doses.

[0031] The present invention will be described in more detail below based on examples, but the present invention is not limited thereto.

[0032] Effects on water transport from the lumen of isolated rat lungs 1. Preparation of lung infusion solution Sodium chloride (127 mmol / L), potassium chloride (5.5 mmol / L), lactic acid (28 mmol / L), magnesium sulfate heptahydrate (1.3 mmol / L), D-(+) glucose (5.5 mmol / L), calcium chloride dihydrate (1.9 mmol / L), bovine albumin (5.1 g / dL), and sodium hydroxide (28 mmol / L) were dissolved in ultrapure water, then diluted to the desired concentration, and the pH was adjusted to 6.8 with 1N hydrochloric acid. 2. Method of preparing the administration solution Compound 1 (Mizagliflozin; Lot. No. S893901, Selex Biotech Co., Ltd.) was adjusted to a concentration of 50 μM in the lung infusion solution. 3. Following the method of Suzuki et al. (Suzuki, Satoshi et al., Japanese Journal of Thoracic Disease, 1996, 34, 1, pp. 52-56), SD rats (male, 9 weeks old, 12 rats, Nippon SLC Co., Ltd.) were quarantined and acclimatized for one week (body weight at time of use: 328-347g), anesthetized with isofran inhalation, and euthanized by total blood collection from the abdominal aorta. Next, the tracheostomy was performed and a nutritional catheter (8fr, Atom Medical Co., Ltd.) was inserted and fixed. Subsequently, the lungs and hearts were removed as a single unit, and 5 mL of lung infusion solution was injected into the control group, while 5 mL of lung infusion solution containing 50 μM compound 1 was injected into the compound 1 administration group at 30 cmH2O. The removed lungs were suspended in 100 mL centrifuge tubes, airtightly contained, and then left to stand in a 37°C constant temperature bath. After 2 hours of incubation, BALF was collected by gravity. The recovered BALF was centrifuged (1000 xg, 5 min, 4°C), and the supernatant was collected and stored at -80°C. The albumin concentration in BALF was measured using the BCG method (TM Shikali Liquid ALB R1, Kanto Chemical Co., Ltd.) with an automated biochemical analyzer (JCA-BM2010, JEOL Ltd.). The glucose concentration in BALF was measured using a self-testing glucose meter (Nipro FS Next™) with a self-testing glucose kit (Nipro FS Blood Glucose Sensor Lite). 4. Data Processing The residual fluid volume in the lungs (Vf) and lung water clearance (LFC) were measured from the measured albumin concentration in BALF using the following formula.Vf = Vi (injection volume) x (injection albumin concentration / BALF albumin concentration) Fwi (injection water fraction) = Vi - amount of albumin in injection Fwf (recovered water fraction) = Vf - amount of albumin in BALF LFC = (Vi x Fwi - Vf x Fwf) / (Vi x Fwi) LFC (%) = LFC x 100 5. Statistical methods Data are shown as mean ± standard deviation, and the change in compound 1 administration group compared to the control group was tested. That is, equal variances were confirmed by the F test, and an unpaired t-test (Student's t-test) was performed. The significance level was set at less than 5% two-sided (*: p < 0.05) and less than 1% two-sided (**: p < 0.01). 6. Spreadsheet and statistical analysis software Microsoft Excel for Microsoft 2021 MSO (Microsoft Corp.) was used for spreadsheet calculations and statistical analysis. 7. Test Results (1) Regarding glucose absorption from the pulmonary lumen, in the control group, 74.7 ± 5.6% of the injected glucose was absorbed from the pulmonary lumen, whereas in the group treated with 50 μM of compound 1, a selective SGLT1 inhibitor, only 9.8 ± 0.7% of the injected glucose was absorbed (p < 0.01). This shows that the selective SGLT1 inhibitor strongly controls glucose absorption from the pulmonary lumen, indicating that SGLT1, which is present in the pulmonary lumen, plays a major role in glucose absorption from the pulmonary lumen. (2) Compound 1 suppressed the absorption of water coupled to glucose absorption from the pulmonary lumen, reducing the pulmonary lumen water clearance, and the albumin concentration in residual pulmonary fluid decreased with the increase in pulmonary lumen water (Table 1).

[0033] The results of Example 1 showed that Compound 1, an SGLT1 selective inhibitor, selectively inhibited SGLT1, which is present in the pulmonary lumen (particularly airway epithelial cells and alveolar epithelial cells) and plays an important role in glucose absorption from the pulmonary lumen. This suppressed water absorption from the pulmonary lumen, significantly reducing pulmonary lumen water clearance and increasing the pulmonary lumen water volume. The compound showed an effect of improving airway mucus hydration and mucociliary transport clearance, suggesting that SGLT1 selective inhibitors, including Compound 1 (KGA-2727, JTT-662, LX2761, etc.), are useful for the prevention or treatment of respiratory diseases and symptoms such as cystic fibrosis, which are impaired mucociliary transport clearance.

[0034] The values ​​of albumin concentration (g / dL) in residual pulmonary fluid and pulmonary water clearance (%) for the control group and the compound 1 (50 μM) treatment group in Example 1 are shown below. (Table 1) Albumin concentration in residual pulmonary fluid and pulmonary water clearance

Claims

1. A pharmaceutical composition comprising an SGLT1 selective inhibitor as an active ingredient for the prevention or treatment of respiratory diseases involving impaired mucociliary transport clearance.

2. The pharmaceutical composition according to claim 1, wherein the SGLT1 selective inhibitor contains 3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole-4-ylmethyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide or a pharmaceutically acceptable salt thereof as an active ingredient.

3. The pharmaceutical composition according to claim 2, wherein the salt contains bis[3-(3-{4-[3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole-4-ylmethyl]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide] monosebacate (Mizagliflozin) as an active ingredient.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the respiratory disease in which mucociliary transport clearance is impaired is at least one disease selected from the group consisting of cystic fibrosis, chronic obstructive pulmonary disease (COPD), chronic bronchitis, emphysema, bronchiectasis (including non-cystic fibrotic bronchiectasis), chronic respiratory tract infection, diffuse panbronchiolitis, sinobronchial syndrome, bronchial asthma, and primary ciliary dysfunction.

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