A pharmaceutical product containing an enteropeptidase inhibitor as an active ingredient for the prevention and / or treatment of polycystic kidney disease, or polycystic liver disease as a complication thereof.

Abstract

To provide pharmaceuticals, etc., for the prevention and / or treatment of polycystic kidney disease, or polycystic liver disease as a complication thereof. [Solution] In this application, as one embodiment of the invention, a pharmaceutical product for the prevention and / or treatment of polycystic kidney disease is disclosed, comprising an enteropeptidase inhibitor as an active ingredient.

Description

[Technical Field]

[0001] The present invention provides, in its embodiments, a pharmaceutical product containing an enteropeptidase inhibitor as an active ingredient for suppressing and / or improving cyst formation in subjects suffering from polycystic kidney disease, or for suppressing and / or improving kidney volume increase based on the suppression and / or improvement of said cyst formation; a pharmaceutical product containing an enteropeptidase inhibitor as an active ingredient for preventing and / or treating polycystic kidney disease, or polyhepatic cysts as a complication thereof; and the like, which are useful in the field of pharmaceuticals. [Background technology]

[0002] Polycystic kidney disease (PKD) is a genetic disorder characterized by the development of numerous cysts in both kidneys, and it is the most common genetic kidney disease. It is broadly classified into autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) based on the causative gene, but most patients have ADPKD. Epidemiological surveys estimate the number of ADPKD patients in Japan to be 31,000 (1 in 4,033). ADPKD is primarily caused by PKD1 and PKD2 genes, with approximately 85% of patients developing the disease due to a PKD1 gene mutation. Polycystin 1 / 2, the gene product of PKD1 / 2, is a membrane protein localized in the cilia of tubular epithelial cells, sensing the flow of urine within the tubules and absorbing calcium into the cell. 2+ The diameter of the renal tubule is regulated by allowing calcium to flow in. In ADPKD, loss of polycystin 1 / 2 function leads to the loss of calcium in the renal tubular epithelial cells. 2+The concentration decreases. As a result, abnormal cell proliferation, tubular dilation, and increased secretion of cystic fluid are triggered, leading to the progressive formation of numerous cysts in both kidneys, and a gradual decrease in glomerular filtration rate (GFR), an indicator of renal function. Most ADPKD patients are asymptomatic until around the age of 30-40, but symptoms associated with renal cyst enlargement appear thereafter, and by the age of 70, about half of patients reach end-stage renal failure. The most common subjective symptom is kidney pain (60%), which can be caused by cystic bleeding, cystic infection, urinary tract stones, or stretching of the renal capsule. Other known complications include hypertension, multiple hepatic cysts, heart valve disease, and cerebral aneurysms.

[0003] Currently, there is no cure for ADPKD, and tolvaptan, a vasopressin type 2 receptor antagonist, is the only treatment approved by insurance for the purpose of slowing its progression. However, its therapeutic effect is not sufficient, and due to concerns about serious side effects, in Japan, its prescription is restricted to patients with a total bilateral renal volume of 750 mL or more and a renal volume increase rate of 5% or more per year. A post-marketing surveillance study that collected data from 1672 clinical cases showed that the incidence of side effects was 46.47%, with hypernatremia reported in 5.56% of patients and liver dysfunction or liver damage in 12.74%. In addition, 60 patients (3.59%) discontinued the drug due to insufficient efficacy, and 318 patients (19.0%) discontinued it due to adverse events. Furthermore, because this drug induces rapid water diuresis due to its mechanism of action, at least the initial administration should be performed under hospitalization, and appropriate fluid intake should be instructed to prevent dehydration. For hypertension, a complication of hepatic hepatitis, restriction of salt intake and administration of angiotensin receptor blockers or angiotensin-converting enzyme inhibitors are recommended. On the other hand, there is no treatment for polycystic hepatic hepatitis, and tolvaptan is ineffective. As described above, the existing drug tolvaptan has problems with efficacy and safety, and its use is limited to certain patients. Therefore, there is a need to develop a new therapeutic agent with a novel mechanism of action that can be applied to a wider range of patients. In cystic epithelial cells of ADPKD patients, the expression of mTOR (mammalian Target of Rapamycin), a serine / threonine kinase involved in cell proliferation and metabolism, is upregulated, and its excessive activation is known to be involved in the progression of ADPKD (Non-Patent Literature 1). In fact, mTOR inhibitors suppress cyst formation and renal function decline in animal models of polycystic kidney disease (Non-Patent Literature 2). Therefore, clinical trials using mTOR inhibitors have been conducted in ADPKD patients, but no efficacy was observed, and development has been discontinued (Non-Patent Literature 3-4). In the everolimus trial, total kidney volume significantly decreased at 1 year of treatment, but the significant difference disappeared at 2 years of treatment, and no improvement in GFR, an indicator of renal function, was observed. However, mTOR inhibitors have a high incidence of side effects, and in this trial, 33% of the active drug group discontinued the trial. In addition, side effects affecting renal hemodynamics, such as edema, occurred, suggesting that drug-induced side effects may have worsened renal function. Furthermore, the inability to sufficiently increase the dosage due to concerns about side effects is considered to be one of the reasons why efficacy was not observed (Non-Patent Literature 2). Therefore, a clear conclusion has not been reached regarding whether mTOR inhibition is useful in the treatment of ADPKD due to issues with the compounds.

[0004] On the other hand, gene expression analysis of cystic tissue from ADPKD patients and kidney tissue from healthy individuals has reported that in ADPKD patients, impaired mitochondrial function leads to compensatory glycolysis, resulting in increased mTOR activity due to decreased AMP-activated protein kinase (AMPK) activity (Non-Patent Literature 5). Therefore, based on the concept of suppressing glucose utilization or utilizing ketone bodies, the usefulness of calorie-restricted diets and ketogenic diets as dietary therapy for ADPKD patients has been investigated in recent years, and a certain inhibitory effect on the increase in total kidney volume and decrease in GFR has been observed (Non-Patent Literature 6). Both dietary therapies are assumed to involve the suppression of mTOR through AMPK activation as a mechanism, and these test results suggest that mTOR may be one of the promising therapeutic targets for ADPKD. However, continuous dietary restriction places a heavy burden on patients and leads to a decline in quality of life, so its implementation in clinical practice is considered to be limited in ADPKD, which requires long-term therapeutic intervention, and intervention with drug therapy that places less burden on patients is desired. In recent years, a link between amino acid-mediated regulation of mTOR activity and ADPKD has been reported. Branched-chain amino acids (BCAAs), particularly leucine, are known to activate mTOR among the nutrients contained in the diet. Furthermore, decreased activity of the BCAA metabolic pathway has been reported in ADPKD patients, suggesting that BCAAs tend to accumulate and mTOR activation by BCAAs is more likely to occur (Non-Patent Literature 5). In fact, when BCAAs were dissolved in the drinking water of ADPKD model mice and BCAA intake was increased, renal mTOR signaling was significantly activated and renal cyst formation was promoted, suggesting that amino acids absorbed from the diet may be involved in cyst formation (Non-Patent Literature 7). Therefore, inhibiting the activation of mTOR signaling by dietary amino acids may be effective in treating ADPKD, but the challenge remains as to how to achieve a reduction in amino acid levels through drug intervention rather than dietary restriction and how to link this to treatment, and a solution has not yet been found.

[0005] Enteropeptidase is a transmembrane serine protease specifically expressed on the luminal side of the duodenum, and it has the physiological effect of cleaving and activating trypsinogen in pancreatic juice into trypsin. Activated trypsin breaks down proteins in food into amino acids, which are then absorbed into the body. Therefore, enteropeptidase is the rate-limiting enzyme in the digestion and absorption of proteins, and it is thought that inhibiting the enzymatic activity of enteropeptidase suppresses the digestion and absorption of proteins in food. Consequently, enteropeptidase inhibitors may be effective in treating polycystic kidney disease by inhibiting the absorption of amino acids into the body after meals and inhibiting the activation of mTOR signaling by amino acids. However, although various enteropeptidase inhibitors have been reported to date (Patent Documents 1-6), while all of them are described as useful for anti-diabetic and anti-obesity purposes, there are absolutely no suggestions or reports that they are effective for polycystic kidney disease. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] International Publication No. 2015 / 122187 [Patent Document 2] International Publication No. 2016 / 158788 [Patent Document 3] International Publication No. 2016 / 104630 [Patent Document 4] International Publication No. 2011 / 071048 [Patent Document 5] International Publication No. 2019 / 088270 [Patent Document 6] International Publication No. 2019 / 216742 [Non-patent literature]

[0007] [Non-Patent Document 1] Proc Natl Acad Sci USA.2006,103(14):5466-5471 [Non-Patent Document 2] Kidney Res Clin Pract.2012,31(3):132-138 [Non-Patent Document 3] N Engl J Med.2010,363(9):830-840 [Non-Patent Document 4] N Engl J Med. 2010,363(9):820-829 [Non-Patent Document 5] Int J Mol Sci.2024,25(13):7173 [Non-Patent Document 6] Cell Rep Med.2023,4(11):101283 [Non-Patent Document 7] Kidney Int. 2017, 92(2):377-387 [Overview of the Initiative] [Problems that the invention aims to solve]

[0008] As mentioned above, drug prevention or treatment methods for ADPKD are not yet established, and there is a need for the development of preventive or therapeutic agents with different mechanisms of action from existing drugs and high clinical efficacy. Similarly, effective prevention or treatment methods for ARPKD have not been established, and there is a similar need in the medical field as there is for ADPKD. Accordingly, the object of the present invention is to provide a pharmaceutical product, etc., for the prevention and / or treatment of polycystic kidney disease, or polycystic liver disease as a complication thereof. [Means for solving the problem]

[0009] As a result of extensive and diligent studies under such circumstances, the present inventors have found, as detailed in the Examples section described later, in tests using an enteropeptidase inhibitor, that the agent suppresses renal mTOR activity, inhibits renal hypertrophy and cyst formation, and unexpectedly also suppresses liver hypertrophy and cyst formation. Based on this new finding, the present inventors have completed the present invention, which provides the enteropeptidase inhibitor for use in the prevention or treatment of polycystic kidney disease, or the combined prevention or treatment of polycystic liver disease as a complication thereof, and the like. Hereinafter, the present invention will be specifically described based on embodiments, but the present invention is not limited to these in any way. Those skilled in the art can modify the embodiments of the present invention into various aspects without departing from the gist of the present invention, and such modifications are also included within the scope of the present invention.

[0010] [1] A medicament for suppressing and / or ameliorating cyst formation in a subject suffering from polycystic kidney disease, or suppressing and / or ameliorating an increase in renal volume based on the suppression and / or amelioration of said cyst formation, comprising an enteropeptidase inhibitor as an active ingredient. [2] The medicament according to [1], which is for improving renal function. [3] The medicament according to the above [1] or [2], which is for preventing and / or treating polycystic kidney disease. [4] The medicament according to any one of the above [1] to [3], which is for preventing and / or treating polycystic kidney disease and polycystic liver disease as a complication thereof in combination. [5] The medicament according to the above [3] or [4], wherein the polycystic kidney disease is ADPKD (autosomal dominant polycystic kidney disease) or ARPKD (autosomal recessive polycystic kidney disease).

[0011] [6] The pharmacopoeia described in any of [1] to [5] above, wherein the enteropeptidase inhibitor is selected from a compound or salt thereof, or a hydrate thereof, described in any of the International Publications 2015 / 122187, 2016 / 158788, 2016 / 104630, 2011 / 071048, 2019 / 088270, or 2019 / 216742. [7] The pharmaceutical product according to any of [1] to [5] above, wherein the enteropeptidase inhibitor is selected from the compounds or salts thereof described in International Publication No. 2015 / 122187, or hydrates thereof. [8] Enteropeptidase inhibitors are described in International Publication No. 2015 / 122187, formula (I):

[0012] [ka]

[0013] [In the formula, Ring A consists of halogen atoms and C 1-6 It represents a benzene ring which may be substituted with one to three substituents selected from alkyl groups; R 1 C is a hydrogen atom or a carbon atom substituted with COOH. 1-6 It shows an alkyl group, R 2 C may be substituted with one or two COOH groups and further substituted with SO3H. 1-6 This indicates an alkyl group. Compounds represented by or their salts, or hydrates thereof, A pharmaceutical product according to any of the above [1] to [5], which is a compound selected from or a salt thereof, or a hydrate thereof. [9] Enteropeptidase inhibitors include N-(((3S)-6-((4-carbamimidoamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid (Example 1), as described in International Publication No. 2015 / 122187. N-(((3R)-6-((4-carbamimidoamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid (Example 2), N-((6-((4-carbamimidoamidebenzoyl)oxy)-4-methyl-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid (Example 3), and their salts, or their hydrates, A pharmaceutical product according to any of the above [1] to [5], which is a compound selected from or a salt thereof, or a hydrate thereof.

[10] Enteropeptidase inhibitors The pharmaceutical product described in any of the above [1] to [5], which is N-(((3S)-6-((4-carbamimidamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid or a salt thereof, or a hydrate thereof.

[11] Enteropeptidase inhibitors The pharmaceutical product described in any of the above [1] to [5], which is N-(((3S)-6-((4-carbamimidamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid hydrate (Example 12 of International Publication No. 2015 / 122187).

[0014]

[12] A method for inhibiting and / or improving cyst formation, or inhibiting and / or improving kidney volume increase based on such inhibition and / or improvement of cyst formation, in a subject suffering from polycystic kidney disease, comprising administering an effective amount of an enteropeptidase inhibitor to the subject.

[13] The method described in

[12] above, for the purpose of improving kidney function.

[14] A method for the prevention and / or treatment of polycystic kidney disease, comprising administering an effective dose of an enteropeptidase inhibitor to a subject in need of such administration.

[15] The method according to

[14] above, for the prevention and / or treatment of polycystic kidney disease and polycystic liver disease as a complication thereof. [Effects of the Invention]

[0015] The present invention provides, as embodiments thereof, a pharmaceutical product containing an enteropeptidase inhibitor as an active ingredient for suppressing and / or improving cyst formation in subjects suffering from polycystic kidney disease, or for suppressing and / or improving kidney volume increase based on the suppression and / or improvement of said cyst formation; a pharmaceutical product containing an enteropeptidase inhibitor as an active ingredient for preventing and / or treating polycystic kidney disease, or polyhepatic cysts as a complication thereof; and the like. [Modes for carrying out the invention]

[0016] Some embodiments of the present invention include the following forms: [A] A pharmaceutical product containing an enteropeptidase inhibitor as an active ingredient for the suppression and / or improvement of cyst formation in subjects suffering from polycystic kidney disease, or for the suppression and / or improvement of kidney volume increase based on the suppression and / or improvement of cyst formation. [A-1] A medicine described in [A] for the purpose of improving kidney function. (The above will also be collectively referred to as "Embodiment A") [B] A pharmaceutical product containing an enteropeptidase inhibitor as an active ingredient for the prevention and / or treatment of polycystic kidney disease. [B-1] The medicine described in [B] above for the prevention and / or treatment of polycystic kidney disease and polycystic liver disease as a complication thereof. [B-2] The pharmaceutical product described in [B] or [B-1] above, wherein the polycystic kidney disease is ADPKD (autosomal dominant polycystic kidney disease) or ARPKD (autosomal recessive polycystic kidney disease). (The above will also be collectively referred to as "Embodiment B")

[0017] The embodiments described above will be explained below by specifically defining the technical meaning of the terms used to specify the technical matters of each embodiment, but the present invention is not limited to these embodiments. Those skilled in the art can modify the embodiments of the present invention in various ways without departing from the meaning of the present invention, and such modifications will also be included within the scope of the present invention. Unless otherwise specified herein, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains.

[0018] (Regarding enteropeptidase inhibitors) Enteropeptidase is a transmembrane serine protease specifically expressed on the luminal side of the duodenum, and it has the physiological effect of cleaving and activating trypsinogen in pancreatic juice into trypsin. In the embodiments described above, "enteropeptidase inhibitor" refers to all compounds that inhibit the function of enteropeptidase. Many "enteropeptidase inhibitors" are already known in the art, and to those skilled in the art, "enteropeptidase inhibitor" is recognized and widely used as a comprehensive technical term referring to this group of compounds. In the above embodiments, a person skilled in the art can appropriately select a preferred enteropeptidase inhibitor from the viewpoint of efficacy, safety, etc. Such enteropeptidase inhibitory activity can be confirmed according to methods known in the art.

[0019] Examples of such enteropeptidase inhibitors include compounds, salts thereof, or hydrates thereof selected from those described in International Publication No. 2015 / 122187, International Publication No. 2016 / 158788, International Publication No. 2016 / 104630, International Publication No. 2011 / 071048, International Publication No. 2019 / 088270, or International Publication No. 2019 / 216742. Here, preferred enteropeptidase inhibitors include those selected from the compounds or salts thereof described in International Publication No. 2015 / 122187, or their hydrates. More preferred enteropeptidase inhibitors include those described in International Publication No. 2015 / 122187, Formula (I):

[0020]

Chemical Formula

[0021] [wherein, Ring A represents a benzene ring which may be substituted with 1 to 3 substituents selected from a halogen atom and C 1-6 alkyl group; R 1 represents a hydrogen atom, or a C alkyl group substituted with COOH 1-6 , R 2 represents a C alkyl group which is substituted with 1 or 2 COOH, and may further be substituted with SO3H 1-6 .] a compound represented by or a salt thereof, or a hydrate thereof, a compound selected from or a salt thereof, or a hydrate thereof, may be mentioned, Further preferred enteropeptidase inhibitors include those described in International Publication No. 2015 / 122187, N-(((3S)-6-((4-carbamimidamidobenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid (Example 1), N-(((3R)-6-((4-carbamimidamidobenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid (Example 2), N-((6-((4-carbamimidamidobenzoyl)oxy)-4-methyl-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid (Example 3), and salts thereof, or hydrates thereof, a compound selected from or a salt thereof, or a hydrate thereof, may be mentioned, Even more preferred enteropeptidase inhibitors include, Examples include N-(((3S)-6-((4-carbamimidoamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid or its salts or hydrates, The most preferred enteropeptidase inhibitor is, An example is N-(((3S)-6-((4-carbamimidamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid hydrate (described in Example 12 of the above-mentioned International Publication No. 2015 / 122187).

[0022] In this specification, "halogen atoms" include, for example, fluorine, chlorine, bromine, and iodine. In this specification, "C 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0023] In the embodiments described above, the "enteropeptidase inhibitor" can be used in either a free form or a salt thereof (preferably a pharmaceutically acceptable salt thereof). Those skilled in the art can appropriately select from both forms to implement the present invention, taking into account the characteristics of each individual enteropeptidase inhibitor used. Examples of salts that are acceptable as pharmaceuticals include salts with inorganic acids such as hydrochloride, hydrobromide, sulfate, and phosphate; salts with organic acids such as acetate, fumarate, oxalate, citrate, methanesulfonate, benzenesulfonate, tosylate, and maleate; and salts with bases such as alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt; and salts with amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.

[0024] If an enteropeptidase inhibitor has isomers such as optical isomers, stereoisomers, positional isomers, or rotational isomers, it can be used as one of the isomers or as a mixture thereof. If an enteropeptidase inhibitor has optical isomers, it is preferable to use the optical isomers separated from the racemate. These isomers can be obtained as individual optical isomers by known synthesis methods, separation methods (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.), optical resolution methods (e.g., fractional recrystallization, chiral column chromatography, diastereomerization, etc.). Enteropeptidase inhibitors may be crystalline, and may be a single crystalline form or a mixture of crystalline forms. Crystals can be produced by crystallization using known crystallization methods. The enteropeptidase inhibitor may be a solvate (e.g., hydrate, etc.) or a solvate (e.g., nonhydrate, etc.), and either can be used in the embodiment described above.

[0025] Enteropeptidase inhibitors can also be used in the form of their prodrugs. Those skilled in the art can design such prodrugs as appropriate, and such prodrugs can be manufactured by methods known to the art. Such prodrugs may be converted into the target enteropeptidase inhibitor under physiological conditions, as described on pages 163 to 198 of Volume 7, Molecular Design, of "Pharmaceutical Development," published by Hirokawa Shoten in 1990.

[0026] (Regarding the function of enteropeptidase inhibitors) As detailed in the Examples section below, it has become clear that enteropeptidase inhibitors can suppress and / or improve cyst formation in the kidney (or kidney and liver) in subjects suffering from polycystic kidney disease. Polycystic kidney disease is a disease primarily caused by the formation of numerous cysts in the kidneys. Therefore, enteropeptidase inhibitors are effective in suppressing and / or improving cyst formation in individuals with polycystic kidney disease, i.e., suppressing cyst formation and / or reducing the number of cysts and / or reducing cyst size. Here, "inhibition of cyst formation" refers to the function of suppressing the progression of cyst formation and preventing cyst formation itself, "reduction in the number of cysts" refers to the function of eliminating some of the formed cysts, and "reduction in cyst size" includes both the function of reducing the size of formed cysts and the function of suppressing the increase in the size of formed cysts. Enteropeptidase inhibitors can suppress and / or improve renal volume enlargement based on the suppression and / or improvement of cyst formation described above. Here, "suppression of renal volume enlargement" refers to the function of stopping or delaying the progression of renal volume enlargement, and "improvement of renal volume enlargement" refers to the function of reducing the enlarged renal volume. Enteropeptidase inhibitors are useful, for example, in improving renal function by performing the functions described above.

[0027] (Regarding the target diseases for enteropeptidase inhibitors) Enteropeptidase inhibitors can be used for the prevention and / or treatment of polycystic kidney disease because they perform the functions described above. Furthermore, they can also be used for the prevention and / or treatment of polycystic liver disease, a complication of polycystic kidney disease. Examples of polycystic kidney disease include ADPKD and ARPKD.

[0028] "Prevention" includes preventing the onset (or recurrence) of a disease (the whole condition or symptoms, or one or more conditions or symptoms) and delaying the onset (or recurrence) of the disease. "Prophylactic effective dose" means a dose of enteropeptidase inhibitor sufficient to achieve this objective.

[0029] "Treatment" includes the cure of a disease (the entire condition or symptoms, or one or more conditions or symptoms), improvement of the disease, and suppression of the progression of the disease's severity. "Therapeutic dose" means a dose of enteropeptidase inhibitor sufficient to achieve such objectives.

[0030] (Regarding the target recipients of the treatment) In the above embodiments, an appropriate enteropeptidase inhibitor is selected and used from the viewpoint of efficacy, safety, etc. Therefore, enteropeptidase inhibitors can be safely administered to mammals (e.g., humans, monkeys, dogs, horses, etc.) (especially to humans).

[0031] (Regarding the route of administration) Enteropeptidase inhibitors may be administered orally or parenterally (e.g., intravenously, by infusion, intramuscularly, subcutaneously, intra-organally, intranasally, intradermally, transdermally, ophthalmally, intracerebrally, intrarectally, intravaginally, intraperitoneally, and to lesions) either alone or as part of a pharmaceutical composition.

[0032] (Regarding dosage) The dosage of enteropeptidase inhibitors varies depending on the target patient, route of administration, and the patient's age and symptoms, but is not particularly limited. For example, the dosage of the active ingredient, the enteropeptidase inhibitor, is 1 to 750 mg, preferably 10 to 500 mg, per oral dose. This dosage can be administered 1 to 3 times a day. When administered in the form of a sustained-release formulation, it is also possible to administer it every other day or at longer intervals to match this dosage.

[0033] (Regarding the form of administration) Enteropeptidase inhibitors can be used either alone or in the form of a pharmaceutical composition containing the enteropeptidase inhibitor as an active ingredient (in one embodiment, as a single active ingredient) together with a pharmaceutically acceptable carrier. In this specification, both forms will be collectively referred to as "medicine."

[0034] Examples of such pharmaceutical compositions include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (including soft capsules and microcapsules), lozenges, syrups, liquids, emulsions, suspensions, controlled-release formulations (e.g., immediate-release formulations, sustained-release formulations, sustained-release microcapsules), aerosols, films (e.g., orally disintegrating films, oral mucosal adhesive films), injections (e.g., subcutaneous injections, intravenous injections (e.g., boluses), intramuscular injections, intraperitoneal injections), drip infusions, transdermal formulations, ointments, lotions, patches, suppositories (e.g., anal suppositories, vaginal suppositories), pellets, nasal formulations, pulmonary formulations (inhalants), eye drops, and the like.

[0035] As "pharmaceutical carriers," various carriers commonly used in the field of pharmaceutical technology can be used. Specific examples of "pharmaceutical carriers" include, for example, in solid dosage forms, excipients (e.g., lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light anhydrous silicic acid, etc.), lubricants (e.g., magnesium stearate, talc, colloidal silica, etc.), binders (e.g., crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose, etc.) and disintegrants (e.g., starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, L-hydroxypropylcellulose, etc.).

[0036] In liquid formulations, solvents (e.g., sterile water for injection, isotonic saline, alcohol, propylene glycol, macrogol, sesame oil, etc.), solubilizers (e.g., polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (e.g., surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, glyceryl monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, etc.), isotonic agents (e.g., glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol, etc.), buffers (e.g., buffers such as phosphates and citrates), and analgesics (e.g., benzyl alcohol, etc.) can be used.

[0037] If necessary, further formulation additives such as preservatives (e.g., parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, sorbic acid, etc.), antioxidants (e.g., sulfites, ascorbic acid, α-tocopherol, etc.), colorants, and sweeteners may be added.

[0038] The pharmaceutical composition may vary depending on the dosage form, administration method, carrier, etc., but it can be manufactured by adding an enteropeptidase inhibitor at a rate of typically 0.01 to 99% (w / w), preferably 0.1 to 85% (w / w), relative to the total amount of the formulation. The pharmaceutical composition can be manufactured by methods conventional in the field of pharmaceutical technology, depending on its form. The pharmaceutical composition may be formed into a controlled-release formulation such as a rapid-release formulation or a sustained-release formulation containing the active ingredient.

[0039] (Regarding concomitant use with other drugs) In implementing the above embodiments, enteropeptidase inhibitors can be used in combination with other drugs to prevent and / or treat the target disease, and excellent preventive and / or therapeutic effects can be expected through combination therapy with other drugs. Furthermore, it is expected that such combination therapy can reduce the dosage of other drugs and thus reduce their side effects. Drugs that can be used in combination with such enteropeptidase inhibitors (hereinafter sometimes abbreviated as "combination drugs") can be appropriately selected in consideration of the type of disease the patient has, the severity of its symptoms, etc. For example, concomitant use with vasopressin V2 receptor antagonists (e.g., tolvaptan), somatostatin analogs (e.g., octreotide, pasireotide, etc.), retinoic acid receptor α subtype agonists (e.g., tamibarotene), microRNA inhibitors (e.g., farabrusen), anti-pregnancy-related plasma protein-A monoclonal antibodies (e.g., ABBV-CLS-628), angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, delapril, etc.), angiotensin II antagonists (e.g., candesartan, losartan, eprosartan, valsartan, telmisartan, irbesartan, olmesartan, azilsartan, etc.), SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin, ipragliflozin, canagliflozin, etc.), and biguanide antidiabetic drugs (e.g., metformin, etc.) is possible. The administration method of the concomitant drug is not particularly limited, and the enteropeptidase inhibitor and the concomitant drug may be combined at the time of administration. For example, it can be used in the following forms: (1) administration of a formulation containing a combination of the enteropeptidase inhibitor and the concomitant drug; (2) simultaneous or separate administration of two formulations obtained by separately formulating the enteropeptidase inhibitor and the concomitant drug via the same route of administration; or (3) simultaneous or separate administration of two formulations obtained by separately formulating the enteropeptidase inhibitor and the concomitant drug via different routes of administration. The preferred form can be appropriately selected according to the actual situation in the medical field. A preparation containing the above-mentioned enteropeptidase inhibitor in combination with a concomitant drug can be manufactured by a person skilled in the art in accordance with the pharmaceutical composition containing the enteropeptidase inhibitor described above. The dosage of concomitant medications may be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of enteropeptidase inhibitors to concomitant medications may be appropriately selected depending on the target disease or symptoms, route of administration, and type of concomitant medication used. Generally, this can be determined appropriately based on the general clinical dose of the concomitant medication used, in accordance with the actual conditions of the medical setting.

[0040] Other embodiments of the present invention include the following forms: [C] A method for inhibiting and / or improving cyst formation, or inhibiting and / or improving kidney volume increase based on such inhibition and / or improvement of cyst formation, in a subject suffering from polycystic kidney disease, comprising administering an effective amount of an enteropeptidase inhibitor to the subject. [C-1] The method described in [C] for the purpose of improving kidney function. [D] A method for the prevention and / or treatment of polycystic kidney disease, comprising administering an effective amount of an enteropeptidase inhibitor to a subject in need of such administration. [D-1] The method according to [D] above, for the prevention and / or treatment of polycystic kidney disease and polycystic liver disease as a complication thereof. [D-2] The method according to [D] or [D-1] above, wherein polycystic kidney disease is ADPKD or ARPKD.

[0041] For details regarding the technical aspects that define the above embodiments, such as "enteropeptidase inhibitor," "functions performed by the enteropeptidase inhibitor," "target diseases," "target populations," "dosage," "route of administration," and "form of administration," refer to the corresponding descriptions of the technical aspects in Embodiments A and B. [Examples]

[0042] The present invention will be described in more detail below with reference to examples, but these examples do not limit the scope of the present invention in any way. Furthermore, unless otherwise specified, the reagents, apparatus, and materials used in the present invention are commercially available or can be prepared appropriately by those skilled in the art.

[0043] Example 1: Human enteropeptidase inhibitory activity In this example, compounds described in International Publication No. 2015 / 122187 were used. Compounds 1 to 11 of the examples described in that publication (the compound in Example 12 is a hydrate of the compound in Example 1) have been shown to have excellent enteropeptidase inhibitory activity (Test Example 1).

[0044] Example 2: Evaluation of the effect of suppressing the rise in postprandial blood amino acid concentration using ADPKD model mice. Pkd1 at 10-12 days old flox / floxMx1-Cre mice were intraperitoneally administered 2.5 μg / g polyinosinate:polycytidylic acid (InvivoGen) for 6 consecutive days to induce deletion of the Pkd1 gene. At some point between 28 and 90 days postnatal, the mice were fasted for 3 hours and orally administered either a solution of test compound 12 (N-(((3S)-6-((4-carbamimidamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid hydrate suspended in 0.5% methylcellulose (compound administration group, 10 or 30 mg / kg) or a 0.5% methylcellulose solution (control group), as representative of the enteropeptidase inhibitors described in the above-mentioned International Publication No. 2015 / 122187. Here, test compound 12 is the hydrate of test compound 1, and the preparation was carried out so that the equivalent amount as test compound 1 was the target dose. One hour later, a 2.5 g / kg protein solution (SAVAS Whey Protein 100, Meiji Co., Ltd.) was orally administered. Blood samples were taken before administration of the protein solution and at 0.5 and 1.5 hours after administration. Serum BCAA concentration was measured by enzymatic method as an indicator of amino acid absorption into the body (BCAA assay kit, Cell Biolabs). The area of ​​the serum BCAA concentration-time curve (AUC) from before administration to 1.5 hours after administration was calculated, and the percentage increase in postprandial serum amino acid concentration was calculated using the following formula. Percentage increase in postprandial blood amino acid concentration (%) = (AUC of the control group ÷ AUC of the control group) × 100 The results are shown in Table 1. The significance of each test group compared to the control group was evaluated by Dunnett's test, and the significance level compared to the control group is indicated as *: p<0.05, **: p<0.01.

[0045] [Table 1]

[0046] As is clear from Table 1, test compound 12 was shown to suppress postprandial protein absorption into the body and lower blood amino acid concentrations in ADPKD model mice.

[0047] Example 3: Evaluation of cyst formation inhibitory effect using ADPKD model mice 10-day-old Pkd1 flox / flox Mx1-Cre mice were intraperitoneally administered 10 μg / g polyinosinic acid:polycytidylic acid (Sigma-Aldrich) for 6 consecutive days to induce deletion of the Pkd1 gene. Subsequently, from 4 weeks of age, the mice were fed either a standard diet (MF, Oriental Yeast Co., Ltd.) or a diet mixed with test compound 12, a representative enteropeptidase inhibitor described in the above-mentioned International Publication No. 2015 / 122187, at rates of 0.003% and 0.01% (w / w). Here, test compound 12 is a hydrate of test compound 1, and it was prepared so that the equivalent amount as test compound 1 was the target dose. At the end of the 4-week administration period, the mice were anesthetized, and after perfusion with 4% paraformaldehyde, the kidneys and livers were collected and weighed. Tissue weight / body weight (%) was calculated using the body weight at necropsy using the following formula. Tissue weight / body weight (%) = (tissue weight ÷ body weight) × 100 Furthermore, each tissue sample was embedded in paraffin, stained with hematoxylin and eosin, and then stained section images were obtained using an all-in-one fluorescence microscope (BZ-X710, Keyence Corporation). The cystic index (CI) was calculated using the following formula. CI (%) = (Total cyst area ÷ Total tissue area) × 100 Furthermore, kidney tissue was solubilized with homogenization buffer (20 mM Tris-HCl, 150 mM NaCl, 1 (v / v)% Triton X-100, protein inhibitor cocktail (Roche Life Sciences), phosphatase inhibitor cocktail (Sigma-Aldrich)), 100 μg of tissue fluid was separated by SDS-PAGE, and transferred to a polyvinylidene fluoride (PVDF) membrane. The PVDF membrane was immersed in 5 (w / v)% skim milk for 1 hour, and then incubated overnight with p-S6 (Ser235 / 236) or a primary antibody against S6 (Cell Signaling Technology). Next, the PVDF membrane was incubated with a secondary antibody conjugated with horseradish peroxidase. After washing, the chemiluminescence obtained from the target protein was detected using SuperSignal West Femto Maximum Sensitivity Substrate (Thermo Fischer Scientific) and ImageQuant LAS4000 (GE Healthcare). The expression level of phosphorylated S6 protein was calculated using the optical density of the bands obtained with primary antibodies for p-S6 (Ser235 / 236) and S6, according to the following formula. p-S6 / S6 (ratio) = p-S6 (optical density of the band of Ser235 / 236) / optical density of the band of S6 Table 2 shows the results for tissue weight / body weight, CI, and p-S6 / S6 (ratio). The significance of each test group compared to the control group was evaluated by Dunnett's test, and the significance level compared to the control group is indicated as *: p<0.05, **: p<0.01.

[0048] [Table 2]

[0049] As is clear from Table 2, test compound 12 reduced p-S6 / S6, an indicator of mTOR activation, in ADPKD model mice, and was shown to suppress the progression of renal hypertrophy and renal cysts. Furthermore, in addition to its effects on the kidneys, test compound 12 also showed an inhibitory effect on the progression of hepatomegaly and hepatic cysts. These test results clearly demonstrate that test compound 12, and other enteropeptidase inhibitors represented by it, are useful for the prevention or treatment of ADPKD. Furthermore, the above test results suggest that enteropeptidase inhibitors are useful for preventing and / or treating polycystic kidney disease, a disease primarily caused by cyst formation in the kidneys, or polycystic liver disease as a complication thereof. [Industrial applicability]

[0050] The present invention provides, in its embodiments, a pharmaceutical product containing an enteropeptidase inhibitor as an active ingredient for suppressing and / or improving cyst formation in subjects suffering from polycystic kidney disease, or for suppressing and / or improving kidney volume increase based on said suppression and / or improvement of cyst formation; a pharmaceutical product containing an enteropeptidase inhibitor as an active ingredient for preventing and / or treating polycystic kidney disease, or polyhepatic cysts as a complication thereof; and the like, which are useful in the field of pharmaceuticals.

Claims

1. A pharmaceutical product containing an enteropeptidase inhibitor as an active ingredient, for the purpose of suppressing and / or improving cyst formation in subjects suffering from polycystic kidney disease, or for suppressing and / or improving kidney volume increase based on said suppression and / or improvement of cyst formation.

2. The pharmaceutical product according to claim 1, for the purpose of improving kidney function.

3. The pharmacopoeia according to claim 1, for the prevention and / or treatment of polycystic kidney disease.

4. The pharmaceutical product according to claim 3, for the prevention and / or treatment of polycystic kidney disease and polycystic liver disease as a complication thereof.

5. The pharmaceutical product according to claim 3 or 4, wherein the polycystic kidney disease is ADPKD (autosomal dominant polycystic kidney disease) or ARPKD (autosomal recessive polycystic kidney disease).

6. The pharmaceutical product according to any one of claims 1 to 4, wherein the enteropeptidase inhibitor is selected from a compound or salt thereof, or a hydrate thereof, described in any of the following International Publications: International Publication No. 2015 / 122187, International Publication No. 2016 / 158788, International Publication No. 2016 / 104630, International Publication No. 2011 / 071048, International Publication No. 2019 / 088270, or International Publication No. 2019 / 216742.

7. The pharmaceutical product according to any one of claims 1 to 4, wherein the enteropeptidase inhibitor is selected from compounds described in International Publication No. 2015 / 122187, or salts thereof, or hydrates thereof.

8. Enteropeptidase inhibitors are described in International Publication No. 2015 / 122187, Equation (I): 【Chemistry 1】 [In the formula, Ring A consists of a halogen atom and C １－６ It represents a benzene ring which may be substituted with one to three substituents selected from alkyl groups; R １ C is a hydrogen atom or a carbon atom substituted with COOH. １－６ It shows an alkyl group, R ２ It is replaced by one or two COOH groups, and furthermore, SO ３ C may be substituted with H. １－６ This indicates an alkyl group. Compounds represented by or their salts, or hydrates thereof, A pharmaceutical product according to any one of claims 1 to 4, which is a compound selected from or a salt thereof, or a hydrate thereof.

9. Enteropeptidase inhibitors are described in International Publication No. 2015 / 122187, N-(((3S)-6-((4-carbamimidamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid, N-(((3R)-6-((4-carbamimidamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid, N-((6-((4-carbamimidamidebenzoyl)oxy)-4-methyl-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid, and their salts, or their hydrates, A pharmaceutical product according to any one of claims 1 to 4, which is a compound selected from or a salt thereof, or a hydrate thereof.

10. Enteropeptidase inhibitors, The pharmaceutical product according to any one of claims 1 to 4, wherein N-(((3S)-6-((4-carbamimidamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid or a salt thereof, or a hydrate thereof.

11. Enteropeptidase inhibitors, The pharmaceutical product according to any one of claims 1 to 4, wherein the pharmaceutically acceptable agent is N-(((3S)-6-((4-carbamimidamidebenzoyl)oxy)-2,3-dihydro-1-benzofuran-3-yl)acetyl)-L-aspartic acid hydrate.

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