Preventive and / or therapeutic drugs for diabetic nephropathy

Abstract

To provide drugs capable of preventing or treating diabetic nephropathy.SOLUTION: Provided is a prophylactic and / or therapeutic drug for diabetic nephropathy comprising a RARγ agonist as an active ingredient. Also provided are a prophylactic and / or therapeutic agent for renal anemia, a drug that suppresses the expression of type IV collagen in mesangial cells, an agent that suppresses expression of BMP4 in mesangial cells, and an agent that suppresses fibrosis in renal tubulointerstitium.SELECTED DRAWING: Figure 2C

Description

[Technical Field]

[0001] The present invention relates to a preventive and / or therapeutic agent for diabetic nephropathy. [Background technology]

[0002] Carbohydrates such as starch are one of the most important nutrients that sustain our lives. When carbohydrates are digested, they become glucose, which is then taken up from the blood into cells throughout the body and used as the main source of energy. Glucose in the blood is called blood sugar, and when carbohydrates are ingested through food, blood sugar levels rise. Conversely, when glucose is consumed as energy through exercise, blood sugar levels fall. In healthy people, blood sugar levels are controlled within a certain range by the balance of insulin and hormones that have the opposite effect to insulin, so blood sugar levels do not fluctuate greatly even when eating or exercising.

[0003] Diabetes is a condition in which blood sugar levels are high due to insufficient insulin action and ineffective use of glucose, and if left untreated, various effects will occur. Diabetes is divided into four types depending on the cause: type 1 diabetes, type 2 diabetes, other diabetes due to specific causes, and gestational diabetes. Of these, type 2 diabetes is the most important in terms of the number of patients.

[0004] Type 2 diabetes occurs due to factors such as insufficient insulin secretion or poor insulin function. It is primarily seen in middle-aged and older people, but in recent years, the number of cases among younger people has been increasing. In Japan, approximately 90% of diabetes patients are said to have type 2 diabetes. Type 2 diabetes is thought to develop when a genetic predisposition is combined with lifestyle factors such as overeating (especially high-fat foods), lack of exercise, obesity, stress, and aging. Furthermore, even if you are not obese, you are more likely to develop the disease if you develop a condition called metabolic syndrome, in which visceral fat increases.

[0005] Type 2 diabetes develops without the patient even noticing and progresses slowly, so the disease may progress without any symptoms. If blood sugar control is not performed due to the absence of symptoms, the following complications may occur.

[0006] Complications can be broadly divided into microangiopathy and macroangiopathy. Microangiopathy is a complication characteristic of diabetes that occurs in small blood vessels and includes three types: diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy (known as the three major complications of diabetes). Macroangiopathy is a complication caused by arteriosclerosis, a disease of large blood vessels, and can be divided into stroke, myocardial infarction, and peripheral arterial disease (such as gangrene of the foot).

[0007] According to the Ministry of Health, Labor and Welfare's 2016 "National Health and Nutrition Survey" (http: / / www.seikatsusyukanbyo.com / statistics / 2017 / 009436.php) (Non-Patent Document 1), the proportion of people "strongly suspected of having diabetes" was estimated to be 12.1%, or approximately 10 million people. In addition, the proportion of people "for whom the possibility of having diabetes cannot be ruled out" was also estimated to be 12.1%, or approximately 10 million people. In other words, the number of people with diabetes and those at risk of developing diabetes was estimated to be approximately 10 million people each.

[0008] According to the International Diabetes Federation (IDF) (Diabetes Atlas No. 7: http: / / www.diabetesatlas.org / ) (Non-Patent Document 2), the global diabetic population continues to grow explosively. As of 2015, the number of people with diabetes reached 415 million, an increase of 28.3 million from the previous year. Furthermore, without effective countermeasures, the number is predicted to increase to 642 million by 2040. The diabetes prevalence rate among adults aged 20-79 in 2015 was 8.8%, meaning that an estimated 1 in 11 people had diabetes. Diabetes-related medical costs amounted to approximately $673 billion, accounting for 5-20% of total medical expenditures in major countries worldwide. Medical costs for diabetes are projected to increase to $802 billion by 2040.

[0009] As mentioned above, the explosive increase in the number of diabetes patients and the resulting explosive increase in medical costs have become a major global problem, leading to the development of a variety of diabetes treatments. Among these, the main treatments for diabetes are glycemic control and antihypertensive therapy. Glycemic control is based on a low-calorie diet and exercise therapy, but antidiabetic drugs (DPP-4 inhibitors, GLP-1 receptor agonists, SGLT2 inhibitors, sulfonylureas, α-glucosidase inhibitors, biguanides, rapid-acting insulin secretagogues, insulin sensitizers, combination drugs, etc.) and insulin injections may also be used. Antihypertensive therapy includes the administration of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, in some cases, other types of antihypertensive drugs such as calcium channel blockers and diuretics.

[0010] Among the three major complications of diabetes, diabetic nephropathy, as symptoms progress, causes waste products to accumulate in the blood, leading to serious, life-threatening conditions such as renal failure and uremia. Renal failure then necessitates dialysis. In recent years, diabetic nephropathy accounts for more than 40% of the underlying disease in new cases of dialysis therapy (http: / / www.jsdt.or.jp / overview_confirm.html) (Non-Patent Document 3), a trend that has remained roughly stable since 2008 (Illustrated: Current Status of Chronic Dialysis Therapy in Japan, as of December 31, 2014; published by the Japanese Society for Dialysis Therapy, December 1, 2015).

[0011] In Japan, as of 2016, there were approximately 320,000 dialysis patients, and the number continues to increase at a rate of 5,000 per year. The rate of increase in the number of patients roughly matches the rate of aging, and is expected to continue growing until 2025. The national treasury pays approximately 5 million yen per dialysis patient per year, for a total of 1.6 trillion yen by simple calculation. Furthermore, dialysis patients often suffer from complications, and if these are included, approximately 2 trillion yen (5% of Japan's total medical expenses) is spent on dialysis patients, making controlling the number of dialysis patients one of the urgent issues facing the medical economy. In contrast, growth hormone (GH) / insulin-like growth factor (IGF1) system inhibitors (Curr Diabetes Rev (2011) 7(1) 50 (Non-Patent Document 4)), Jak / Stat system inhibitors (Diabetologia (2016) 59,1624 (Non-Patent Document 5); Diabetes (2009) 58, 469 (Non-Patent Document 6); Nephrol Dial Transplant (2015) 30, iv54 (Non-Patent Document 7)), CCL2=MCP1 / CCR2 antagonists (Biochem Biophys Res Commun (2007) 360,772 (Non-Patent Document 8); Diabetes Care (2009) 32(3) 465 (Non-Patent Document 9)), Nrf2-Keap1 system activators (N Engl J Med (2013) 369 (26) 2492 (Non-patent document 10); Nephrol Dial Transplant (2013) 28, 2841 (Non-patent document 11); N Engl J Med (2011) 365 (4) 327 (Non-patent document 12); Am J Physiol Renal Physiol (2013) 304, F808 (Non-patent document 13)), Notch1 system inhibitor (Nephrol Dial Transplant (2015) 30, iv54 (Non-patent document 7)), ET A There have been reports of the treatment of diabetic nephropathy using R antagonists (Nephrol Dial Transplant (2015) 30, iv54 (Non-Patent Document 7)), but the effects are not satisfactory.

Prior Technology Literature

Non-licensed literature

[0012]

Non-licensed literature 1

Non-licensed Document 2

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Direct Environment 7

Outdoor Track 8

Outdoor Tools9

Outdoor Tools 10

[0013] An object of the present invention is to provide a drug capable of preventing or treating diabetic nephropathy. [Means for solving the problem]

[0014] Therefore, based on the mechanism of onset of diabetic nephropathy discovered by the inventors, the inventors have developed a therapeutic agent for diabetic nephropathy, discovered a candidate therapeutic agent, and completed the invention.

[0015] Diabetic nephropathy is a type of microvascular disorder caused by chronic hyperglycemia. Pathologically, it manifests as thickening of the glomerular vascular basement membrane and expansion of the mesangial area. Clinically, it manifests as proteinuria (microalbuminuria), hypertension, edema, and other symptoms, ultimately leading to renal failure due to glomerular sclerosis. Furthermore, in diabetes, abnormalities such as arteriosclerosis and tubulointerstitial degeneration and fibrosis are observed in tissues other than the glomerulus, further exacerbating glomerular lesions. Thus, nephropathy can be defined as a pathological condition characterized by the gradual progression of proteinuria, hypertension, and renal dysfunction after a certain period of diabetes. The present inventors have demonstrated that the nuclear transcription factor Smad1, a downstream molecule of ALK (activating receptor-like kinase), a type I receptor of the TGF-β superfamily, directly activates the type IV collagen α1 and α2 chain genes, and that these factors are the most important causative molecules for the expansion of the glomerular mesangial matrix in diabetic nephropathy. 1,2 Smad1 is the most important factor inducing mesangial matrix expansion in STZ (streptozotocin)-induced diabetic rats 3 Furthermore, various studies have shown that the Smad1 signaling pathway is strongly associated with the pathogenesis of diabetes in animal models. 4-10 .

[0016] Furthermore, the present inventors have found that activation of the Smad1 signaling pathway via the BMP4 (bone morphogenetic protein 4) / ALK3 pathway plays an important role in mesangial expansion, a pathological hallmark of diabetic nephropathy. 11 The mechanism of action is detailed below. When hyperglycemia persists, the amount of advanced glycation end products (AGEs) in the blood increases. When these AGEs in the blood bind to AGE receptors on mesangial cells, the production of BMP4 in mesangial cells increases. When BMP4 binds to the ALK3 receptor on mesangial cells, Smad1 is phosphorylated, and two molecules of phosphorylated Smad1 and one molecule of Smad4 form a trimer, which translocates from the cytoplasm to the nucleus and initiates the transcription of type IV collagen, one of its target genes. This increased production of type IV collagen leads to an expansion of the mesangial matrix (Figure 1).

[0017] Based on the mechanism of action described above, compounds that inhibit the BMP4 / ALK3 / Smad1 / type IV collagen pathway may be potential preventive and therapeutic agents for diabetic nephropathy. BMP4 / ALK3 is a member of the TGF-β superfamily. 11 Recently, it has been reported that RAR (Retinoic acid receptor) agonists suppress TGF-β signaling. 12 Therefore, we planned to evaluate various RAR agonists.

[0018] RAR has three subtypes: α, β, and γ. Subtype specificity or selectivity of compounds with RAR agonist activity is expected to reduce the risk of side effects (Patent Document 1). Among these, RARα agonists, such as retinoids or 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoic acid, have been disclosed as drugs for the prevention and / or treatment of diabetic retinopathy or age-related macular degeneration (see Patent Documents 2, 3, and 4). Meanwhile, RARγ agonists, such as palovarotene, have been shown to be useful for emphysema, cancer, and skin diseases (Patent Document 5) and for neuropathic pain (Patent Document 6). Furthermore, Patent Document 7 describes the usefulness of palovarotene for muscle repair. However, there have been no reports examining the effects of palovarotene on diabetic nephropathy, nor any literature suggesting this.

[0019] On the other hand, diabetes-induced tubulointerstitial lesions induce fibrosis through TGF-β phosphorylation of Smad2 / 3, which induces αSMA. 13, 14 Tubulointerstitial lesions are one of the pathological conditions that develop as diabetic nephropathy progresses. Previous research has shown that "hyperglycemia and subsequent hemodynamic abnormalities, such as glomerular hyperfiltration and hypertension, which frequently accompany diabetes, ultimately accelerate histological changes, such as a decrease in the number of nephrons and fibrosis of the renal interstitium, leading to the progression of renal failure." 15 " This shows that

[0020] Tubulointerstitial lesions, like glomerular lesions, are important pathological features of diabetic nephropathy. However, to date, few attempts have been made to simultaneously evaluate glomerular and tubulointerstitial lesions to identify more effective preventive and therapeutic agents for diabetic nephropathy. Therefore, we established an in vitro assay system using cultured mesangial cells and searched for small molecule compounds, primarily RARγ agonists, that inhibit the BMP4 / ALK3 / Smad1 / IV collagen pathway or Smad2 / 3 phosphorylation. As a result, we found that RARγ agonists can inhibit these pathways or phosphorylation, thereby completing the present invention. Compounds that can inhibit the BMP4 / ALK3 / Smad1 / IV collagen pathway or Smad2 / 3 phosphorylation are useful for the prevention and / or treatment of diabetes-related complications, particularly diabetic nephropathy. In recent years, it has been suggested that a common mechanism underlying the progression of interstitial fibrosis and the development of renal anemia exists, since at least some of the fibroblasts that form the foci of tubulointerstitial fibrosis are derived from erythropoietin (EPO)-producing cells and lose their EPO-producing ability when transformed into fibroblasts. 14 According to this hypothesis, drugs for preventing and / or treating interstitial fibrosis may be effective drugs for preventing and / or treating renal anemia.

[0021] The gist of the present invention is as follows. (1) A preventive and / or therapeutic agent for diabetic nephropathy, comprising an RARγ agonist as an active ingredient. (2) The preventive and / or therapeutic agent according to (1), wherein the RARγ agonist is at least one compound selected from the group consisting of Palovarotene, 3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid, 4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid, esters thereof, and salts thereof. (3) The preventive and / or therapeutic agent according to (1), wherein the diabetic nephropathy is caused by type 2 diabetes. (4) A preventive and / or therapeutic drug for renal anemia, comprising an RARγ agonist as an active ingredient. (5) A drug containing an RARγ agonist as an active ingredient that suppresses the expression of type IV collagen in mesangial cells. (6) The drug according to (5), wherein the RARγ agonist is at least one compound selected from the group consisting of palovarotene, 4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid, esters thereof, and salts thereof. (7) A drug containing an RARγ agonist as an active ingredient that suppresses the expression of BMP4 in mesangial cells. (8) The drug according to (7), wherein the RARγ agonist is at least one compound selected from the group consisting of Palovarotene, 3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8,-tetrahydronaphthalen-2-yl)acetamido)benzoic acid, esters thereof, and salts thereof. (9) A drug that suppresses fibrosis in the renal tubulointerstitium, containing an RARγ agonist as an active ingredient. (10) The drug according to (9), wherein the RARγ agonist is at least one compound selected from the group consisting of palovarotene, esters of palovarotene, and salts thereof. (11) A drug described in (9) that suppresses the expression of pSmad2 / 3 in tubulointerstitial cells. (12) The drug according to (9), wherein the fibrosis in the renal tubular interstitium is caused by diabetic nephropathy. (13) The drug according to any one of (1) to (12), which is administered orally or parenterally. [Effects of the Invention]

[0022] The RARγ agonists, particularly palovarotene, esters thereof, or salts thereof, which are active ingredients of the preventive and / or therapeutic drug for diabetic nephropathy of the present invention, can suppress fibrosis in the renal tubular interstitium, are useful for preventing or treating the onset of diabetic nephropathy, and may be able to prevent transition to hemodialysis. [Brief explanation of the drawings]

[0023] [Figure 1] FIG. 1 is a schematic diagram showing the molecular mechanism of the development of diabetic nephropathy. [Figure 2A] Effect of Palovarotene on TGF-β production in AGE-stimulated mouse mesangial cells. Each group was treated with (1) no stimulation, (2) AGE 300 μg / mL, (3) AGE 300 μg / mL + Palovarotene 0.5 μM, or (4) AGE 300 μg / mL + Palovarotene 1 μM. RNA was extracted by the AGPC method 24 hours after treatment. [Figure 2B] Effect of Palovarotene on BMP4 production in AGE-stimulated mouse mesangial cells. Each group was treated with (1) no stimulation, (2) AGE 300 μg / mL, (3) AGE 300 μg / mL + Palovarotene 0.5 μM, or (4) AGE 300 μg / mL + Palovarotene 1 μM. RNA was extracted by the AGPC method 24 hours after treatment. [Figure 2C] Effect of palovarotene on type IV collagen (Col4α1) production in AGE-stimulated mouse mesangial cells. Each group was treated with (1) no stimulation, (2) AGE 300 μg / mL, (3) AGE 300 μg / mL + palovarotene 0.5 μM, or (4) AGE 300 μg / mL + palovarotene 1 μM. RNA was extracted by the AGPC method 24 hours after treatment. [Figure 3]Effect of palovarotene on streptozotocin-induced diabetic mice. (1) Ctrl.: Histological results of control mice; (2) Palo. Ctrl.: Histological results of control mice administered palovarotene; (3) DM: Histological results of mice in which diabetes was induced by administration of streptozotocin; and (4) DM+Palo: Histological results of mice in which diabetes was induced by administration of palovarotene. [Figure 4] Effect of palovarotene on unilateral ureteral ligation (UUO) mice as a model of renal tubulointerstitial fibrosis. Control: Histological evaluation of the kidneys of mice without ureteral ligation using Sirius red staining. UUO: Histological evaluation of the kidneys of mice raised for 7 days after ureteral ligation to induce tubulointerstitial fibrosis using Sirius red staining. UUO+Palo: Histological evaluation of the kidneys of mice given 1 mg / kg of palovarotene intraperitoneally for 6 days starting 1 day after ureteral ligation using Sirius red staining. DETAILED DESCRIPTION OF THE INVENTION

[0024] The present invention will be described in detail below. The present invention provides a preventive and / or therapeutic agent for diabetic nephropathy, which comprises an RARγ agonist as an active ingredient.

[0025] The RARγ agonist preferably has the effect of suppressing the BMP4 / ALK3 / Smad1 / type IV collagen pathway.

[0026] As used herein, the term "BMP4 / ALK3 / Smad1 / type IV collagen pathway" refers to a pathway in which BMP4 binds to ALK3 / BMPRII (a type II receptor for BMP), phosphorylates Smad1, and induces the production of type IV collagen. 16Specific examples are shown below: Culturing mesangial cells in the presence of advanced glycation end products (AGEs) increases the production of bone morphogenetic protein 4 (BMP4). Furthermore, binding of BMP4 to the ALK3 / BMPRII receptor on mesangial cells results in phosphorylation of Smad1, resulting in the formation of a trimer consisting of two phosphorylated Smad1 molecules and one Smad4 molecule. This trimer translocates from the cytoplasm to the nucleus and initiates the transcription of type IV collagen, one of its target genes. Since type IV collagen production is known to be the most important factor in mesangial matrix expansion, compounds that inhibit the BMP4 / ALK3 / Smad1 / type IV collagen pathway are considered to be potential therapeutic agents for the prevention and treatment of diabetic nephropathy. Therefore, the present invention provides a drug containing an RARγ agonist as an active ingredient that suppresses the expression of type IV collagen in mesangial cells. The present invention also provides a drug containing an RARγ agonist as an active ingredient that suppresses the expression of BMP4 in mesangial cells.

[0027] The present invention also provides a drug for preventing and / or treating diabetic nephropathy, particularly diabetes-induced tubulointerstitial lesions (particularly fibrosis), which comprises an RARγ agonist as an active ingredient.

[0028] The RARγ agonist preferably has the effect of suppressing signals related to the TGF-β / smad2 / 3 / ECM pathway.

[0029] As used herein, the "TGF-β / Smad2 / 3 / ECM pathway" refers to a pathway in which TGF-β is secreted from glomerular and tubular cells in response to hyperglycemia and AGEs, binds to the TGF-β receptor, promotes phosphorylation of Smad2 / 3, induces excessive accumulation of extracellular matrix (ECM) proteins, and causes tubulointerstitial fibrosis. Smad2 / 3 is thought to be phosphorylated by TGF-β stimulation and functions as a nuclear translocation transcription activator. 17Therefore, the present invention provides a drug that contains an RARγ agonist as an active ingredient and suppresses fibrosis in the renal tubulointerstitium. This drug may suppress the expression of pSmad2 / 3 in tubulointerstitial cells. The fibrosis in the renal tubulointerstitium may be caused by diabetic nephropathy. In recent years, it has been suggested that a common mechanism underlying the progression of interstitial fibrosis and the development of renal anemia exists, since at least some of the fibroblasts that form the foci of tubulointerstitial fibrosis are derived from erythropoietin (EPO)-producing cells and lose their EPO-producing ability when transformed into fibroblasts. 14 According to this hypothesis, it is believed that a preventive and / or therapeutic agent for interstitial fibrosis can be an effective preventive and / or therapeutic agent for renal anemia. Therefore, the present invention also provides a preventive and / or therapeutic agent for renal anemia, which comprises an RARγ agonist as an active ingredient.

[0030] The diabetic nephropathy may be nephropathy resulting from type 2 diabetes. However, the scope of the present invention is not limited thereto. The present invention can be applied to the prevention and / or treatment of various types of diabetic nephropathy.

[0031] The RARγ agonist according to the present invention includes 4-[(E)-2-[5,5,8,8-Tetramethyl-3-(pyrazol-1-ylmethyl)-6,7-dihydronaphthalen-2-yl]ethenyl]benzoic acid (Palovarotene) represented by the following formula (I), 6-[3-(1-Adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (O-Desmethyl Adapalene) represented by the following formula (II), 3-Fluoro-4-(2-hydroxy-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)acetamido)benzoic acid (BMS189961) represented by the following formula (III), and 4-[7-(1-Adamantyl)-6-hydroxynaphthalen-2-yl]benzoic acid (BMS189961) represented by the following formula (IV). Examples include palovarotene, O-desmethyl adalene, BMS189961, CD1530, esters of these compounds (palovarotene, O-desmethyl adalene, BMS189961, CD1530), and salts of these compounds (palovarotene, O-desmethyl adalene, BMS189961, CD1530).

[0032] [ka] Palovarotene

[0033] [ka] O-Desmethyl Adapalene

[0034] [ka] BMS189961

[0035] [ka] CD1530

[0036] Other aspects of the present invention include a method for preventing and / or treating diabetic nephropathy, which comprises administering an RARγ agonist to a subject, an RARγ agonist for use as a preventive and / or therapeutic agent for diabetic nephropathy, and the use of an RARγ agonist in the preparation of a preventive and / or therapeutic agent for diabetic nephropathy. Further aspects of the present invention include a method for preventing and / or treating renal anemia, which comprises administering an RARγ agonist to a subject, an RARγ agonist for use as a preventive and / or therapeutic agent for renal anemia, and the use of an RARγ agonist in the preparation of a preventive and / or therapeutic agent for renal anemia.

[0037] Palovarotene, which can be used as one of the active ingredients of the preventive and / or therapeutic agent for diabetic nephropathy and / or renal anemia of the present invention, is described in Patent Document 5, and O-Desmethyl Adapalene is described in the following document (Sun S.Y. et al., Cancer Research (2002)). 18 and Patent Document 8, BMS189961 is described in Patent Document 8, and CD1530 is described in the following document (Shimono K. et al., Nat Med. 17(4): 454-460 (2011)). 19 These compounds, their esters, or their salts can be produced according to standard methods or purchased as commercial products. Palovarotene, O-Desmethyl Adapalene, BMS189961, and CD1530 were purchased from Axon Medchem and ApexBio, respectively, and used in the Examples described below.

[0038] The ester of the RARγ agonist, which is the active ingredient of the preventive and / or therapeutic drug for diabetic nephropathy and / or renal anemia of the present invention, is not particularly limited as long as it is an ester that is converted into an RARγ agonist by a reaction with an enzyme or the like under physiological conditions in the body, and examples of such esters include esters with primary alcohols such as methanol, ethanol, propanol, hexanol, and dodecanol; esters with secondary alcohols such as isopropanol, s-butanol, and 1-ethylpropanol; esters with tertiary alcohols such as t-butanol and 1-methyl-1-ethylpropanol; and esters with amino alcohols such as 2-aminoethanol.

[0039] The above esters can be produced from RARγ agonists or synthetic intermediates thereof by known methods.

[0040] The salt of the RARγ agonist, which is the active ingredient of the agent for preventing and / or treating diabetic nephropathy and / or renal anemia of the present invention, is not particularly limited as long as it is a pharmaceutically acceptable salt, and such salts include (1) acid addition salts such as inorganic acid salts of hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, and phosphate; or organic acid salts such as acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, benzenesulfonate, p-toluenesulfonate, glutamate, and aspartate; or (2) basic salts such as metal salts of sodium salt, potassium salt, calcium salt, and magnesium salt; inorganic salts such as ammonium salt; or organic amine salts such as triethylamine salt and guanidine salt.

[0041] The prophylactic and / or therapeutic agents for diabetic nephropathy and / or renal anemia of the present invention can be administered orally or parenterally (intravenously, intramuscularly, intraperitoneally, transdermally, transtracheally, intradermally, or subcutaneously) in the form of tablets, capsules, powders, syrups, granules, fine granules, pills, liquids, suspensions, emulsions, transdermal preparations, suppositories, ointments, lotions, inhalants, or injections, etc., by mixing with appropriate pharmacologically acceptable additives. For example, compositions for oral administration include solid or liquid dosage forms, specifically tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups, emulsions, suspensions, etc. Such compositions can be prepared by conventional methods and may contain carriers, diluents, or excipients commonly used in the pharmaceutical field. For example, carriers and excipients for tablets include lactose, starch, sucrose, magnesium stearate, and the like.

[0042] Compositions for parenteral administration include, for example, injections and suppositories. Injections may be in the form of intravenous, subcutaneous, intradermal, intramuscular, or drip infusion injections. Such injections are prepared by conventional methods, i.e., by dissolving, suspending, or emulsifying an RARγ agonist in a sterile aqueous or oily liquid typically used for injections. Aqueous solutions for injection include physiological saline, isotonic solutions containing glucose or other adjuvants, and the like. These solutions may be used in combination with suitable solubilizers, such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, polyethylene glycol), and nonionic surfactants (e.g., polysorbate 80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)). Oily solutions include sesame oil and soybean oil, and may be used in combination with solubilizers such as benzyl benzoate and benzyl alcohol. The prepared injections are typically filled into appropriate ampoules. Suppositories for rectal administration can be prepared by mixing a substance that has the effect of suppressing Smad1 expression with a conventional suppository base.

[0043] The above-mentioned oral or parenteral pharmaceutical compositions may be prepared in dosage unit forms suitable for the dosage of the active ingredient, such as tablets, pills, capsules, injections (ampoules), suppositories, etc.

[0044] These preparations are produced by known methods using additives such as excipients, lubricants, binders, disintegrating agents, emulsifiers, stabilizers, flavoring agents, or diluents.

[0045] Examples of the excipient include organic excipients and inorganic excipients. Examples of the organic excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, α-starch, and dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; and pullulan. Examples of the inorganic excipients include light anhydrous silicic acid and sulfates such as calcium sulfate.

[0046] Examples of lubricants include stearic acid; metal stearates such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as beeswax or jasmine; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; D,L-leucine; sodium lauryl sulfate; silicic acids such as silicic anhydride or silicic acid hydrate; or starch derivatives of the above-mentioned excipients.

[0047] Examples of binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, macrogol, and the compounds listed above as excipients.

[0048] Examples of disintegrants include cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, and internally cross-linked carboxymethyl cellulose calcium; cross-linked polyvinylpyrrolidone; and chemically modified starches or cellulose derivatives such as carboxymethyl starch and carboxymethyl starch sodium.

[0049] Examples of emulsifiers include colloidal clays such as bentonite or veegum; anionic surfactants such as sodium lauryl sulfate; cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, and sucrose fatty acid esters.

[0050] Examples of stabilizers include parahydroxybenzoic acid esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; acetic anhydride; or sorbic acid.

[0051] Examples of flavoring agents include sweeteners such as saccharin sodium or aspartame; acidulants such as citric acid, malic acid or tartaric acid; and flavorings such as menthol, lemon extract or orange extract.

[0052] The diluent is a compound commonly used as a diluent, such as lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol, starch, polyvinylpyrrolidone, or a mixture thereof.

[0053] The dosage of the agent of the present invention for preventing or treating diabetic nephropathy and / or renal anemia can be varied as appropriate depending on the dosage form, the severity of the symptoms of the patient to be administered, their age, body weight, the judgment of the physician, etc. In the case of oral preparations, the dosage generally ranges from 0.01 to 5000 mg, preferably 0.1 to 2500 mg, and more preferably 0.5 to 1000 mg, converted into the amount of active ingredient per day for an adult, and can be administered once or in divided doses.

[0054] The preventive and / or therapeutic agent for diabetic nephropathy and / or renal anemia of the present invention is not particularly limited as long as it contains an RARγ agonist as an active ingredient. RARγ agonists, typified by palovarotene, suppress the expression of TGF-β, BMP4, and Col4α1, and are therefore expected to suppress mesangial matrix expansion.

[0055] Based on the above mechanism of action, compounds and protein inhibitors that can inhibit the BMP4 / ALK3 / Smad1 / type IV collagen pathway or the TGF-β / Smad2 / 3 / ECM pathway are expected to have similar effects to palovarotene. For example, Zhang et al. demonstrated that Noggin can suppress BMP4 expression in diabetic mice. 20 Maciel et al. showed that GREM1 can suppress BMP4 activity. 21 Yu et al. demonstrated that Dorsomorphin can inhibit BMP4-induced Smad1 phosphorylation and further demonstrated that Dorsomorphin can inhibit ALK3 or Smad1, which are related targets of the BMP4 signaling pathway. 22 Yu et al. suggested that the optimized molecule LDN-193189 suppresses BMP4-mediated transcriptional activity of Smad1 and ALK3. 23 Xu et al. demonstrated that calmodulin inhibits Smad1 activity by interacting with the N-terminal domain of Smad1. 24 Other studies have also shown that Smad6 suppresses Smad1-associated Runx1 activity, thereby inhibiting the BMP4 signaling pathway. 25On the other hand, previous studies have suggested that chondroitin-4-sulfate (C4S) can inhibit the degradation of type IV collagen. 26 Other inhibitors, such as DMH-1, have been shown by Neely et al. to displace Noggin and inhibit ALK3. 27 , ΔSmad73TEVGR can suppress Smad1 phosphorylation. 28 Table 1 summarizes inhibitors of BMP4, ALK3, Smad1, and type IV collagen, which are important target molecules involved in the BMP4 / ALK3 / Smad1 / type IV collagen pathway.

[0056] Table 1. List of inhibitors of BMP4 / ALK3 / Smad1 / type IV collagen pathway related signals TIFF0007755919000005.tif54169

[0057] On the other hand, Bourgeois et al. showed that overexpression of MAN1 induces dephosphorylation of Smad2 and Smad3. 29 Inhibitors of the TGF-β / smad2 / 3 / ECM pathway are summarized in Table 2.

[0058] Table 2. List of inhibitors of the TGF-β / smad2 / 3 / ECM pathway TIFF0007755919000006.tif99159

[0059] In addition to the above inhibitors, molecules, and signals, substances that can inhibit the BMP4 / ALK3 / Smad1 / type IV collagen pathway or the TGF-β / smad2 / 3 / ECM pathway are expected to have the same effect as the present invention. [Example]

[0060] The present invention will be specifically described below with reference to examples, although the scope of the present invention is not limited to these examples.

[0061] Example 1 <Effects of Palovarotene on Mouse Mesangial Cells> (method) From 4-week-old wild-type C57BL / 6J mice, the method of Davies M et al. (Kidney Int. 1994;45(2):320-7) 36 Glomeruli were isolated and cultured according to the method described in [1]. AGEs for cell stimulation were prepared according to the method described by Doi T et al. (Proc. Nat. Acad. Sci. USA 1992; 89:2873-2877). 37 It was prepared according to the following. Cultured mouse mesangial cells were grown to confluence and serum-starved in Opti-MEM (Invitrogen). After 24 hours, RNA was extracted using the AGPC method. RT-quantitative PCR was performed using the RNA, and mRNA expression levels were assessed using the cycle comparison method (ΔΔCt). The genes evaluated were TGF-β1, BMP4, and Col4α1. The results are shown in Figure 2.

[0062] (result) Based on the finding that RAR agonists suppress TGF-β signaling, we first investigated whether palovarotene suppresses AGE-stimulated TGF-β expression. As shown in Figure 2A, palovarotene strongly suppressed the expression of TGF-β, which was promoted by AGE stimulation. Next, based on the finding that AGE stimulation increases BMP4 expression in mesangial cells, we investigated the effect of palovarotene on BMP4 expression. As shown in Figure 2B, palovarotene dose-dependently suppressed the AGE-induced increase in BMP4 expression, and almost completely suppressed it at a concentration of 1 μM. Furthermore, when examining the effect of Palovarotene on the expression of Col4α1 (type IV collagen), which is a causative factor for the expansion of the mesangium region, it was found that Palovarotene completely suppressed the production of Col4α1 (type IV collagen) increased by AGE stimulation even at a concentration of 0.5 μM (Figure 2C). From the above results, it was suggested that Palovarotene may be able to suppress the expression of type IV collagen via BMP4 / ALK3 by suppressing the expression of BMP4. Therefore, in order to examine this possibility, an evaluation of Palovarotene was carried out using diabetic model mice.

[0063] [Example 2] [Examination of the effect of Palovarotene on STZ-induced diabetic mice] (Method) ICR mice (purchased from Nippon Clea) aged 12 - 15 weeks were intraperitoneally administered (I.P.) 50 mg / kg of streptozotocin (Wako) once a day for 5 consecutive days to induce diabetes. Four weeks after streptozotocin administration, the mice were switched to a high-fat diet HFD60 (Oriental Yeast Co., Ltd.), and Palovarotene was intraperitoneally administered at 60 μg / kg twice a week. After 12 weeks, dissection and histological evaluation were performed. The results are shown in Figure 3.

[0064] (Results) As shown in Figure 3, in diabetic mice (DM) administered streptozotocin, compared with control mice (Ctrl), expansion of the glomerular mesangium region (PAS staining), activation of Smad1 (pSmad1), activation of Smad2 / 3 (pSmad2 / 3), and increased expression of type IV collagen (Col4) were observed. Furthermore, a decrease in the expression area of the intercellular junction molecule nephrin in glomerular podocytes (Nephrin) and a decrease in WT1 expressed in the podocyte cell nucleus (WT1) were observed. The above results indicate that diabetic mice administered streptozotocin are excellent model mice that well reflect the histopathological changes of human diabetic nephropathy. When palovarotene was administered to these diabetic mice (DM+Palo), the expansion of the glomerular mesangial area (PAS staining), the activation of Smad1 (pSmad1), and the expression of type IV collagen (Col4) were suppressed compared to diabetic mice (DM).Furthermore, the decrease in the area of ​​nephrin expression (Nephrin) and the decrease in WT1 expression in the podocyte nuclei (WT1) were also observed. Furthermore, administration of palovarotene to diabetic mice (DM+Palo) was found to strongly suppress Smad2 / 3 phosphorylation compared to diabetic mice (DM). Activation of Smad2 / 3 is an important factor in the progression of diabetes-induced tubulointerstitial lesions. Based on the results of inhibiting Smad2 / 3 phosphorylation, palovarotene was shown to suppress tubulointerstitial fibrosis. Based on these findings, the preventive or therapeutic potential of palovarotene for diabetic nephropathy is demonstrated by suppressing Smad1 phosphorylation in the glomerulus, thereby suppressing glomerular sclerosis, and by suppressing Smad2 / 3 phosphorylation in the interstitium, thereby suppressing interstitial fibrosis.

[0065] Example 3 Effect of Palovarotene on Unilateral Ureteral Obstruction (UUO) Mice as a Model of Renal Tubulointerstitial Fibrosis (method) The unilateral ureter obstruction (UUO) model induces renal interstitial fibrosis in rats with ureteral obstruction for 7 days. Specifically, the kidney is exposed to the peritoneum through a unilateral dorsal incision, and the ureter is ligated at two or three sites with sutures at 1 mm intervals. Ureteral obstruction reduces renal blood flow and glomerular filtration rate. Macrophage infiltration into the tubular interstitium, apoptosis of tubular epithelial cells, and increased interstitial fibrosis are induced by the proliferation of fibroblasts and extracellular matrix proteins. This model induces fibrosis in a short period of time and is highly reproducible without the use of toxic substances, resulting in no uremia. A UUO model was created using 10- to 12-week-old ICR mice (purchased from CLEA Japan). The control group consisted of mice that did not undergo ureteral ligation. The UUO group consisted of mice that were kept in a ureteral ligation state for 7 days to induce renal interstitial fibrosis. The palovarotene group consisted of mice that received intraperitoneal administration of 1 mg / kg palovarotene for 6 consecutive days, starting 1 day after UUO treatment. Mice from each group were dissected 7 days after UUO treatment, and their kidneys were histologically evaluated using Sirius Red staining. Typical histological staining results for each group (two sections per group) are shown in Figure 4.

[0066] (result) As shown in Figure 4, no tubulointerstitial fibrosis was observed in the kidneys of control mice. Seven days after ureteral ligation, the kidneys of UUO mice were stained very strongly with Sirius Red, revealing significant tubulointerstitial fibrosis. Furthermore, when UUO mice were administered palovarotene for 6 days (UUO+Palo), the degree of Sirius Red staining in the tubulointerstitial tissue was significantly milder than in the kidney tissue of UUO mice, demonstrating that palovarotene significantly inhibited tubulointerstitial fibrosis. The hypothesis is that fibroblasts that form foci of tubulointerstitial fibrosis are derived from EPO-producing cells and lose their EPO-producing ability when they transform into fibroblasts. 14 According to this study, palovarotene is thought to be an effective preventive and / or therapeutic agent not only for tubulointerstitial fibrosis but also for renal anemia.

[0067] Example 4 <Comparison of the effects of four RARγ agonists on mouse mesangial cells> (method) According to the method of Example 1, the inhibitory effects of four types of RARγ agonists (palovarotene, O-desmethyl adapalene, BMS189961, and CD1530) on the expression of TGF-β1, BMP4, and Col4α1 were compared.

[0068] (result) The values ​​are expressed as relative values, with the value for "AGE 300 μg / ml + Palovarotene 0.5 μM" being set at 100%. First, we examined the inhibitory effect of RARγ agonists on TGF-β1 expression. As shown in Table 3, palovarotene exhibited a dose-dependent inhibitory effect. CD1530 also exhibited a dose-dependent inhibitory effect, but its effect was weaker than that of palovarotene. O-Desmethyl Adapalene and BMS189961 had weaker inhibitory activity than palovarotene. Next, we investigated the inhibitory effect of BMP4 expression, and found that Palovarotene exhibited a dose-dependent inhibitory effect, as shown in Table 3. However, the other three compounds did not exhibit any inhibitory effect. Furthermore, when the inhibitory effect of Col4α1 (type IV collagen) expression was examined, palovarotene showed a dose-dependent inhibitory effect, as shown in Table 3. CD1530 also showed a dose-dependent inhibitory effect, but the effect was weaker than that of palovarotene. On the other hand, O-Desmethyl Adapalene showed a dose-dependent promoting effect on Col4α1 (type IV collagen) expression. The inhibitory effect of CD1530 was also weaker than that of palovarotene.

[0069] Table 3. Comparison of the inhibitory effects of four RARγ agonists on TGF-β1, BMP4, and Col4α1 production JPEG0007755919000007.jpg85156

[0070] From the above results (Examples 1, 2, 3, and 4), it was found that among RARγ agonists, Palovarotene exhibited the strongest and dose-dependent inhibitory effect on TGF-β, BMP4, and Col4α1 (type IV collagen), which are factors related to the progression of diabetic nephropathy. Therefore, Palovarotene is considered to be a promising preventive or therapeutic drug for diabetic nephropathy. [Cited documents] 1.Doi T, Vlassara H, Kirstein M, Yamada Y, et al. Receptor-specific increase in extracellular matrix production in mouse mesangial cells by advanced glycosylation endproducts is mediated via platelet derived growth factor. Proc Natl Acad Sci USA 1992; 89:2873-2877. 2.Abe H, Matsubara T, Iehara N, et al. Type IV collagen is transcriptionally regulated by Smad1 under advanced glycation end product (AGE) stimulation. J Biol Chem 2004; 279:14201-14206. 3.Matsubara T, Abe H, Arai H, et al. Expression of Smad1 is directly associated with glomerulosclerosis in diabetic nephropathy. Lab Invest 2006; 86:357-68. 4.Mima A, Matsubara T, Arai H, et al. Angiotensin II-dependent Src and Smad1 signaling pathway is crucial for the development of diabetic nephropathy. Lab Invest 2006; 86:927-939. 5.Ohashi S, Abe H, Takahashi T, et al. Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy. J Biol Chem 2004; 279:19816-23. 6.Takahashi T, Abe H, Arai H, et al. Activation of STAT3 / Smad1 is a key signaling pathway for progression to glomerulosclerosis in experimental glomerulonephritis. J Biol Chem 2005; 280:7100-7106. 7.Tominaga T, Abe H, Ueda O, et al. Activation of BMP4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy. J Biol Chem 2011; 286:20109-20116. 8.Kishi S, Abe H, Akiyama H, et al. Sox9 protein induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy. J Biol Chem 2011; 286:32162-32169. 9.Abe H, Tominaga T, Matsubara T, et al. Scleraxis modulates bone morphogenetic protein 4 (BMP4)-Smad1-smooth muscle α-actin (SMA) signal transduction in diabetic nephropathy. J Biol Chem 2012; 287:20430-42. 10. Matsubara T, Araki M, Abe H, et al. Bone morphogenetic protein 4 and Smad1 mediate extracellular matrix production in the development of diabetic nephropathy. Diabetes 2015, 64(8):2978-90. 11.Tominaga T, Abe H, Ueda O, et al. Activation of BMP4 signaling leads to glomerulosclerosis that mimics diabetic nephropathy. J Biol Chem 2011; 286:20109-20116. 12.Pendaries V, Verrcchia F, Michel S, et al. Retinoic acid receptors interfere with the TGF-β / Smad signaling pathway in a ligand-specific manner. Oncogene 2003; 22:8212-8220. 13.Khalil H, Kanisicak O, Prasad V, et al. Fibroblas-specific TGF-β-Smad2 / 3 signaling underlies cardiac fibrosis. The journal of Clinical Investigation 2017; 127(10):3770-3783. 14. 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[Patent Document 1] International Publication No. 2014 / 073209 [Patent Document 2] Retable No. 2007 / 037188 [Patent Document 3] U.S. Publication No. 20160120843 [Patent Document 4] International Publication No. 2014 / 188716 [Patent Document 5] International Publication No. 2002 / 028810 [Patent Document 6] International Publication No. 2008 / 057930 [Patent Document 7] U.S. Publication No. 20140363402 [Patent Document 8] JP 2013-536855 A [Industrial Applicability]

[0071] The present invention can be used for the prevention and treatment of diabetic nephropathy. Furthermore, the RARγ agonist (e.g., palovarotene), which is the active ingredient of the preventive or therapeutic agent for diabetic nephropathy of the present invention, is also useful for suppressing glomerular mesangial expansion, suppressing Smad1 activation, and suppressing type IV collagen.

Claims

1. A drug for suppressing fibrosis in the renal tubulointerstitium, comprising palovarotene or a salt thereof as an active ingredient.

2. The drug according to claim 1, which is administered orally or parenterally.

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