Application of LY2922470 in the manufacture of drugs for the prevention or treatment of kidney disease

Abstract

This invention discloses the application of LY2922470 in the manufacture of drugs for the prevention or treatment of kidney disease. Using an adenine-induced renal failure animal model, the therapeutic effects of LY2922470 and TAK875 on renal injury and renal failure were evaluated. Experimental results showed that LY2922470 was effective in treating renal failure, but the therapeutic effect was not directly related to GPR40 targeting. Using an in vitro renal fibrosis model, it was confirmed that LY2922470 had an inhibitory effect on renal fibrosis.

Description

[Technical Field]

[0001] The present invention relates to the field of biomedical technology, particularly to the application of LY2922470 in the manufacture of drugs for the prevention or treatment of kidney diseases. [Background technology]

[0002] LY2922470 was developed by Eli Lily and Company as a GPR40 small molecule activator to treat type 2 diabetes. Its structure is as follows:

[0003] [ka]

[0004] GPR40 belongs to the GPCR family. It has been demonstrated that activation of GPR40 can induce glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells and incretin secretion in enteroendocrine cells. Therefore, GPR40 has already become a viable and promising therapeutic target for type 2 diabetes. Because it lacks the risk of hypoglycemia, it has attracted considerable attention as a therapeutic target for T2DM. Currently, numerous GPR40 ligands are being developed and investigated for their antidiabetic effects. Among these, TAK-875, a GPR40 activator, has been successfully tested in Phase II trials.

[0005] Patent WO2015105786A1 first proposed the general formula of the LY2922470 compound structure and suggested that the compound could be used to treat type 2 diabetes.

[0006] Renal failure, also known as renal failure, is a syndrome consisting of a decrease in glomerular filtration rate (GFR) due to chronic kidney disease caused by various factors and associated metabolic disorders and clinical symptoms, characterized by a persistent and progressive decrease in glomerular filtration rate. The incidence of chronic kidney failure in Japan is more than 5 in 10,000 of the total population, and there is currently a lack of effective treatments, except for expensive blood dialysis and kidney transplants, making the search for new drugs to treat kidney disease extremely significant.

[0007] Renal fibrosis is considered a common pathway in nearly all types of chronic kidney disease (CKD), affecting the glomerulus, tubules, and renal vasculature. Fibrosis is a hallmark of CKD and is characterized by epithelial-mesenchymal transition (EMT), excessive extracellular matrix (ECM) deposition, and the accumulation of interstitial and inflammatory cells. Through EMT, tubular epithelial cells become myofibroblasts, which have the ability to enhance cell proliferation, motility, contraction, and excessive ECM deposition, thereby causing fibrosis. Injuries such as ischemia-reperfusion (IR), nephrotoxins, chemotherapy drugs, diabetes, hypertension, and ureteral obstruction can all lead to the development of renal fibrosis.

[0008] Transforming growth factor-β1 (TGF-β1) exerts its function by regulating the TGF-β / Smad pathway and can be a global regulator of fibrosis. Therefore, TGF-β1 can be used to induce fibrosis in vitro. Summary of the Invention [Problem to be solved by the invention]

[0009] The technical problem to be solved by the present invention is to provide a new indication for the drug LY2922470. As a drug for kidney disease, LY2922470 can effectively improve kidney function, providing a new preliminary drug for the prevention and treatment of kidney damage, chronic kidney disease and renal failure.

[0010] The technical means of the present invention is the application of LY2922470 in the manufacture of a drug for preventing or treating kidney disease, The structural formula of LY2922470 is shown below.

[0011] [ka]

[0012] Further, the kidney disease is kidney damage, chronic kidney disease or kidney failure.

[0013] Furthermore, the kidney disease is a kidney disease caused by kidney fibrosis.

[0014] Furthermore, said kidney disease includes nephropathy due to ischemia-reperfusion (IR), nephrotoxins, chemotherapy drugs, hypertension or ureteral obstruction or diabetic nephropathy.

[0015] Furthermore, in the medicine, LY2922470 is present in the form of a compound or a pharmaceutically acceptable salt thereof.

[0016] Furthermore, the medicine is in oral or injectable dosage form, including powder, tablet, granule, capsule, oral liquid, emulsion or suspension.

[0017] Furthermore, the medicine further includes an auxiliary agent or a medicine for protecting the kidneys and blood vessels.

[0018] Additionally, the drug further comprises a pharmaceutically acceptable carrier, including a diluent, buffer, suspending agent, emulsion, granule, encapsulating agent, excipient, filler, adhesive, spray, transdermal agent, wetting agent, disintegrant, absorption enhancer, surfactant, colorant, flavoring agent, or adsorption carrier.

[0019] In the present invention, the drug contains an effective dose of LY2922470. The effective dose is in the form of a unit dosage (e.g., the content of one tablet, one needle, one pill, or one drug) or a unit dose (e.g., a unit body weight dose) for the patient to be treated. In the present invention, the therapeutic target range of the drug is mammals, including humans, canines, rodents, etc. The effective dose conversion for different animals can be calculated based on the equivalent dose conversion relationship between experimental animals and humans in the field (usually referring to the guidance of drug regulatory agencies such as the FDA and SFDA, and also referring to "Huang Jihan et al., Equivalent Dose Conversion Between Animals and Animals and Humans in Pharmacological Experiments," Chinese Clinical Pharmacology and Therapeutics, 2004 Sep, 9(9):1069-1072"). For example, for commonly used laboratory animals, mice, the conversion relationship with adults is approximately 12:1 according to the above literature.

[0020] In the present invention, it was revealed that the effective dose (based on content) for treating adenine-induced renal failure in 8-week-old C57BL / 6N mice is 20 to 100 mg / kg, preferably 30 to 60 mg / kg.

[0021] Preferably, when the adult body weight standard is 60 kg based on the effective dose conversion relationship between mice and adults, the effective dose for an adult is 100 to 500 mg, preferably 150 to 300 mg per day. [Effects of the Invention]

[0022] Compared with the prior art, the present invention has the following beneficial effects: The present invention evaluated the therapeutic effects of LY2922470 and TAK875 on renal injury and renal failure using an adenine-induced renal failure animal model. The experimental results showed that LY2922470 was effective in treating renal failure, but the therapeutic effect was not directly related to GPR40 targeting. Using an in vitro renal fibrosis model, LY2922470 was confirmed to have an inhibitory effect on renal fibrosis. This invention demonstrates the significant potential of LY2922470 as a kidney disease drug, and for the first time, LY2922470 effectively improves renal function, providing a new potential alternative drug effective in the treatment of renal injury, chronic kidney disease, and renal failure, expanding the indications of LY2922470 and significantly improving its potential applications and market prospects. [Brief explanation of the drawings]

[0023] [Figure 1] is the glomerular filtration rate of a model mouse constructed by feeding it with a model diet containing 0.25% adenine for 3 weeks. [Figure 2] The changes in creatinine (CREA) in adenine-induced mouse renal failure model (*P<0.05, **P<0.01, ***P<0.0001). [Figure 3] 1 shows the survival curve for mice treated with adenine-induced renal failure using LY2922470. [Figure 4] is the glomerular filtration rate in mice with adenine-induced renal failure treated continuously with LY2922470. [Figure 5] is the glomerular filtration rate in mice with adenine-induced renal failure treated with LY2922470 for two weeks. [Figure 6] This is a statistical chart of the degree of renal fibrosis (semi-quantitative analysis by MASSON staining) when mice with adenine-induced renal failure were treated with LY2922470. [Figure 7] The graph shows the quantitative results of RT-PCR of fibrosis markers induced by TGF-β1 in HK-2 cells by LY2922470. [Figure 8]The graph shows the quantitative results of RT-PCR of fibrosis markers in HK-2 cells induced by hyperglycemia caused by LY2922470. DETAILED DESCRIPTION OF THE INVENTION

[0024] The experimental methods used in the following examples are conventional unless otherwise specified. The experimental materials used in the following examples can be purchased from commercial sources unless otherwise specified.

[0025] Example 1: Successful construction of adenine-induced mouse kidney injury and renal failure model 1. Experimental materials Experimental animals: C57BL / 6N, 8 weeks old, SPF grade, male, provided by Siberian (Beijing) Biotechnology Co., Ltd.

[0026] 2. Method for constructing a mouse model of renal injury and renal failure (adenine-induced) Except for the control group, the remaining mice were fed with a model diet containing 0.25% adenine to establish the model. The blank control group was fed with normal diet and the mice were allowed to eat freely for three weeks, and at the end of the third week, the glomerular filtration rate and related renal function indicators were measured.

[0027] 3. Experimental Results and Conclusions As shown in Figure 1, the glomerular filtration rate of mice in the control and adenine-induced renal failure model groups was significantly lower in mice fed a 0.25% adenine-containing diet than in mice fed a normal diet (P<0.001), resulting in almost complete loss of glomerular filtration function. Changes in creatinine (CREA) concentration are primarily determined by glomerular filtration capacity (glomerular filtration rate). As filtration capacity decreased, creatinine concentrations increased. Figure 2 shows the CREA levels in the control and model groups, which corresponded relatively accurately to the condition in which the kidneys were substantially damaged. Compared to the control group, CREA levels in the model group mice were significantly elevated (P<0.001). This matched the pathophysiological symptoms of renal failure mice, successfully establishing a renal failure model.

[0028] Example 2: LY2922470 effectively reduces mouse mortality due to renal failure 1. Experimental materials 1. Experimental animals: C57BL / 6N, 8 weeks old, SPF grade, male. 2. Experimental drugs: LY2922470 (Shanghai Ceramic Biology Co., Ltd.), TAK875 (Shanghai Ceramic Bio Co., Ltd.). 1) Preparation method of TAK875: 27 mg of TAK875 powder was taken using a precision balance, dissolved in 9 ml of 0.8% CMC-Na solution, and ultrasonically cleaned for 5 minutes to prepare a 3 mg / ml white suspension. This was then stored at 4°C as a reserve. 2) Preparation of LY2922470: 80 mg of yellow crystalline LY2922470 was added to 200 μL of DMSO solution to prepare a clear yellow solution. This was then added to 10 mL of 0.8% CMC-Na solution in batches, and after 5 hours of ultrasonic heating, an 8 mg / mL white suspension of LY2922470 was prepared. Both were stored at 4°C as spares.

[0029] II. Experimental Group Assignment and Administration

[0030] [Table 1]

[0031] Note: po means oral administration, QD means once a day.

[0032] 3. Experimental process Eight-week-old C57BL / 6N male mice were selected and adaptively housed for one week, then randomly divided into six groups. Except for the blank control group, the remaining mice were fed a model diet containing 0.25% adenine to construct the model. The blank control group was fed regular chow. The mice ate ad libitum. One week after model construction, the mice from each group were divided into experimental groups and administered intragastrically. The blank control and model groups were administered the solvent under the same conditions once every afternoon. The mice continued to be housed on the adenine diet during the administration period, and the survival status of the mice was recorded until the end of the experiment.

[0033] 4. Experimental results and conclusions Table 1 shows the survival rate statistics for the LY2922470-induced adenine-induced mouse renal failure model. Figure 3 shows the corresponding survival rate line graph. No mice died during the 19 days of adenine feeding. However, weight loss and physique gradual weakening occurred in all groups. Deaths began to occur on the 20th day of feeding the adenine-containing diet, with all mice dying by the 27th day in the LY-10 mg / kg group. The control group had a 100% survival rate, the model group had a 14.3% survival rate, the TAK875-treated group had a 46.20% survival rate, and the LY-60 mg / kg and TAK875 groups had survival rates approaching 50%. LY2922470 exerted the strongest protective effect on the kidneys at a dose of 30 mg / kg, with a final survival rate of 100%—double that of the TAK875 group.

[0034] The data in the table show that LY2922470 has therapeutic effects at doses of 30 mg / kg / d to 60 mg / kg / d, with the best therapeutic effect on renal failure at 30 mg / kg / d. However, the protective effect on renal function at doses <30 mg / kg / d (e.g., 20 to 30 mg / kg) is not eliminated, nor is the therapeutic effect on renal failure at doses >60 mg / kg / d, e.g., 60 to 100 mg / kg, eliminated.

[0035] [Table 2]

[0036] Example 3: Therapeutic Effects of LY2922470 on Renal Damage and Renal Failure

[0037] 1. Experimental materials 1. C57BL / 6N, 8 weeks old, SPF grade, male 2. Experimental drugs: LY2922470, TAK875 (both purchased from Shanghai Taoshu Biological Co., Ltd.).

[0038] 2. Experimental group a) Control group: Raised on adenine-free diet, and the remaining procedures were the same as those of the model group. b) Model group: Model construction by raising them on a diet containing 0.25% adenine c) LY-10mg / kg group: Model + LY2922470(10mg / kg,po,QD) d) LY-30mg / kg group: Model + LY2922470(30mg / kg,po,QD) e) LY-60mg / kg group: Model + LY2922470(60mg / kg,po,QD) f) TAK875 group: Model + TAK875 (30mg / kg,po,QD) Note: po means oral administration, QD means once a day.

[0039] III. Experimental Method 1. Experimental process For model construction, mice were fed a 0.25% adenine-containing model diet, with the exception of the blank control group. The blank control group was fed a normal diet and allowed to eat ad libitum. One week after model construction, the mice were administered intragastrically once daily in the afternoon for two consecutive weeks. The blank control and model groups were administered the vehicle under the same conditions. During the treatment period, the mice were maintained on the adenine diet until the end of the experiment. The mice were observed throughout the experiment and weighed weekly. Blood was collected from the fundus at one and three weeks (two weeks of treatment) after model construction, and serum CRE and BUN were measured. After two weeks of treatment, renal function tests were performed on each group of mice using the TGFR renal function monitoring and intelligent analysis system. After the test, the mice were subjected to in vivo measurements to confirm the efficacy of the drug.

[0040] 2. Data collection and statistical analysis Statistical analysis was performed using GraphPad software and Prism 8.0 statistical software. Data for each group of measurement data was expressed as mean ± SD. Comparisons between multiple groups were performed using one-way ANOVA, and comparisons between two groups were performed using t-tests, with p<0.05 considered to indicate a statistically significant difference. Comparisons between groups of enumeration data were performed using chi-square tests, with p<0.05 considered to indicate a statistically significant difference.

[0041] 4. Experimental results and conclusions 1. Glomerular filtration rate Figure 4 shows that mice were fed a diet containing 0.25% adenine, and then administered LY2922470 or TAK875 after one week. During the administration period, the mice were fed adenine diet to continue model construction. After three weeks of adenine feeding (two weeks of administration), the mice's glomerular filtration rate was measured using the TGFR renal function monitoring and intelligent analysis system.

[0042] As shown in Figure 4, the glomerular filtration rate of the model mice was significantly lower than that of the control group, and glomerular filtration function was almost completely lost. Compared to the model group, the glomerular filtration rate of the mice was improved after oral administration of the GPR40 agonist TAK875. After oral administration of different doses of LY2922470, the renal function of the mice was all improved, with the improvement in the mice treated with 30 mg / kg of LY2922470 being the most significant.

[0043] Because the renal failure condition in the mouse model constructed using the above 0.25% adenine diet was severe and the renal function damage was severe, the model construction method was redesigned and another experiment was conducted to test the therapeutic effect of LY2922470 on renal failure (the adenine diet was switched to a normal diet after two weeks, with all other factors remaining unchanged). The results are shown in Figure 5. Compared with the model mice, the mice treated with LY2922470 had significantly improved renal function, which was statistically significant (NS: not statistically significant, *p<0.5, *p<0.01, *p<0.001). The results demonstrated that LY2922470 has a therapeutic effect on renal damage and renal failure.

[0044] 2. Kidney function indicators: Creatinine (CREA) and blood urea nitrogen (BUN) The mice were fed a diet containing 0.25% adenine, and one week later, LY2922470 or TAK 875 was administered. During the administration period, the mice continued to be fed adenine diet to continue model construction. After three weeks of adenine feeding (two weeks of administration), the mice's blood was collected, and the serum was separated to detect CREA and BUN. The results of the mouse renal function indicators CREA and BUN for each group are shown in Tables 2 and 3.

[0045] There was no significant difference in renal function between the mice in each group after one week of adenine feeding. After three weeks of model construction (two weeks of treatment), CREA and BUN levels in the model group mice were elevated compared to the blank control group (*p<0.05, *p<0.01 compared to the blank control group). Oral administration of the GPR40 agonist TAK875 did not result in a significant decrease in CREA and BUN levels compared to the model group mice (*p<0.5, *p<0.01, *p<0.001 compared to the model control group). Oral administration of different doses of LY2922470 resulted in a decrease in blood creatinine and urea nitrogen, indicators of renal function. Compared to the model group mice, serum CREA levels in mice treated with 30 mg / kg and 60 mg / kg LY2922470 were significantly decreased, and serum BUN levels in mice treated with 30 mg / kg LY2922470 were statistically significant. Results: LY2922470 showed therapeutic effects on renal injury and renal failure, and this therapeutic effect was not directly related to GPR40 targeting.

[0046] The data in the table show that LY2922470 has therapeutic effects at doses of 30 mg / kg / d to 60 mg / kg / d, with the best therapeutic effect at 30 mg / kg / d. However, this does not exclude the protective effect on kidneys at doses <30 mg / kg / d (e.g., 20 to 30 mg / kg), nor does it exclude the therapeutic effect on kidney disease at doses of 60 mg / kg / kg, e.g., 60 to 100 mg / kg.

[0047] CREA, an index of mouse renal function in each group

[0048] [Table 3]

[0049] BUN, an index of renal function in each group of mice

[0050] [Table 4]

[0051] (Example 4) Inhibitory effect of LY2922470 on renal fibrosis

[0052] 1. Experimental materials Same as Example 3

[0053] 2. Experimental group assignment Same as Example 3

[0054] III. Experimental Method 1. Experimental process Model construction and administration were performed as in Example 3. Two weeks after administration, the mice were euthanized, and the kidneys were fixed, sectioned, Masson stained, and analyzed.

[0055] 2. Data collection and statistical analysis Whole slides were scanned using a fully automated digital pathology section scanner, KF-PRO-120, from Ningbo Jiangfeng Bioinformation Technology Co., Ltd. Masson-stained images were analyzed using the Area Quantification module in HALO software. Blue collagen fiber staining was selected as the standard criterion for positive results, and the images were analyzed to calculate the percentage of blue collagen fibers in the tissue.

[0056] Statistical analysis was performed using GraphPad software and Prism 8.0 statistical software. Data for each group of quantitative data were expressed as mean ± SD. Comparisons between multiple groups were performed using one-way ANOVA analysis. Comparisons between two groups were performed using t-tests, with p<0.05 considered to indicate a statistically significant difference. Comparisons between groups of quantitative data were performed using chi-square tests, with p<0.05 considered to indicate a statistically significant difference.

[0057] 4. Experimental results and conclusions As shown in Figure 6, after 3 weeks of model construction (2 weeks of administration), the degree of renal fibrosis in the model group mice was significantly increased compared to the control group mice. Oral administration of the GPR40 agonist TAK875 did not significantly reduce the degree of fibrosis compared to the model group mice. Oral administration of LY2922470 at a dose of 30 mg / kg / day to mice reduced collagen deposition, inhibited ECM deposition, and alleviated the degree of renal fibrosis. These experimental results demonstrate that LY2922470 can resist renal fibrosis and that its anti-fibrosis effect can be independent of GPR40 targeting.

[0058] (Example 5) Inhibitory effect of LY2922470 on renal fibrosis (TGF-β1-induced fibrosis) 1. Experimental materials

[0059] [Table 5]

[0060] 2. Experimental group assignment A: Control; B: TGF-β1 (10 ng / ml) C: TGF-β1 (10 ng / ml) + LY (10 nM); D: TGF-β1 (10 ng / ml) + LY (50 nM); E: TGF-β1 (10 ng / ml) + LY (500 nM);

[0061] III. Experimental Method HK-2 cell culture medium: MEM + 10% FBS + 1% (Penicillin-Streptomycin Solution). HK-2 cells were removed from liquid nitrogen and rapidly placed in a 37°C water bath. The cryopreservation tube was gently shaken to dissolve the cryopreservation solution. After dissolution, the cells were transferred to a centrifuge tube containing 3 mL of medium and centrifuged to collect the cells. The cells were then centrifuged at room temperature for 5 minutes at 1000 rpm and the supernatant was discarded. The cells were then suspended in complete medium containing 10% fetal bovine serum, inoculated into a Petri dish, gently mixed, and cultured at 37°C under 5% CO2-saturated humidity conditions.

[0062] HK-2 cells in the logarithmic growth phase and in good growth condition were collected and 1*10 5 Cells were cultured in a 24-well plate at 40-50% confluency and treated according to the above groupings. Group A (HK-2) was cultured naturally; Group B (treated with 10 ng / ml TGF-β1); Group C (treated with 10 ng / ml TGF-β1 and 10 nM LY); Group D (treated with 10 ng / ml TGF-β1 and 50 nM LY); and Group E (treated with 10 ng / ml TGF-β1 and 500 nM LY). After 48 hours of culture, each group was sampled for RT-PCR testing. The primer sequences are shown in the table below.

[0063] [Table 6]

[0064] 4. Experimental results The anti-fibrotic effect of LY2922470 was confirmed using a TGF-β1-induced human proximal renal tubular epithelial cell model, HK-2 cells. According to the results of RT-PCR experiments (Figure 7), compared with the Control group, when TGF-β1 was added, the expression levels of the fibrosis markers Fibronectin and α-SMA were significantly increased. When different concentrations of LY were added compared with the TGF-β1 group, the expression levels of Fibronectin and α-SMA were decreased to varying degrees, showing a dose-dependent relationship (*: 0.01 < p < 0.05 compared with the Control group; **: p < 0.01 compared with the Control group; #: 0.01 < p < 0.05 compared with the TGF-β1 group; ##: p < 0.01 compared with the TGF-β1 group).

[0065] (Example 6) Inhibitory effect of LY2922470 on renal fibrosis (hyperglycemia-induced fibrosis)

[0066] I. Experimental materials 1. D-glucose (Shanghai国药) 2. The rest is the same as in Example 5

[0067] II. Grouping of experiments A: Control; B: HG (25 mM) C: HG (25 mM) + LY (10 nM); D: HG (25 mM) + LY (50 nM); E: HG (25 mM) + LY (500 nM);

[0068] III. Experimental methods HK-2 cell medium: MEM + 10% FBS + 1% (Penicillin-Streptomycin Solution). HK-2 cells were taken out from liquid nitrogen and rapidly placed in a 37°C water bath. The cryopreservation tube was gently shaken to dissolve the cryopreservation solution. After dissolution, the cells were transferred to a centrifuge tube containing 3 mL of medium, and the cells were collected by centrifugation. Centrifugation was performed at 1000 rpm for 5 minutes at room temperature, the supernatant was discarded, and the cells were suspended in complete medium containing 10% fetal bovine serum, inoculated into a Petri dish, gently blown to mix, and cultured under conditions of 37°C, 5% CO2, and saturated humidity.

[0069] When the cells reach a density of 40% - 50%, the cells are treated according to the above grouping. Group A HK-2 is cultured naturally, Group B is treated by adding 25 mM of D-glucose high glucose, Group C is treated by adding 25 mM of D-glucose high glucose and 100 nM of TAK, Group D is treated by adding 25 mM of D-glucose high glucose and 10 nM of LY, Group E is treated by adding 25 mM of D-glucose high glucose and 50 nM of LY, Group F is treated by adding 25 mM of D-glucose high glucose and 500 nM. Each group was sampled after 48 h of culture for RT-PCR detection.

[0070] IV. Experimental Results The anti-fibrotic effect of LY2922470 was confirmed using the DMEM-induced HK-2 injury model. According to the results of the RT-PCR experiment (Figure 8), compared with the Control group, when high glucose was added, the expression levels of Fibronectin and α-SMA were significantly increased. Compared with the high glucose group, when different concentrations of LY were added, the expression levels of Fibronectin and α-SMA were decreased to different degrees, showing a dose-dependent relationship (*: 0.01 < p < 0.05 compared with the Control group; **: p < 0.01 compared with the Control group; #: 0.01 < p < 0.05 compared with the TGF-β1 group; ##: p < 0.01 compared with the high glucose group).

[0071] The present invention evaluated the therapeutic effects of LY2922470 and TAK875 on kidney diseases using an adenine-induced kidney injury, a renal insufficiency animal model, and a renal fibrosis in vitro model. The experimental results showed that LY2922470 protects kidney function and has the effect of treating diseases such as kidney injury, chronic kidney disease, and renal insufficiency, and moreover, the therapeutic effect has no direct relationship with the GPR40 target. Using the in vitro models of TGF-β1-induced fibrosis and high glucose-induced fibrosis, it was confirmed that LY2922470 has an anti-fibrotic effect. Therefore, the present invention demonstrated the potential growth potential of LY2922470 as a kidney drug, and LY2922470 has the effect of treating kidney diseases and has broad clinical application prospects.

Claims

1. 1. Use of LY2922470 in the manufacture of a drug for preventing or treating kidney disease, The structural formula of said LY2922470 is shown below. 【Transformation 3】

2. 2. The application of claim 1, wherein the kidney disease is kidney damage, chronic kidney disease or kidney failure.

3. The application according to claim 1, characterized in that the kidney disease is a kidney disease caused by renal fibrosis.

4. 3. The application of claim 2, wherein the kidney disease comprises nephropathy due to ischemia-reperfusion (IR), nephrotoxins, chemotherapy drugs, hypertension or ureteral obstruction, or diabetic nephropathy.

5. The use according to claim 1, characterized in that in the medicine, LY2922470 is present in the form of a compound or a pharmaceutically acceptable salt thereof.

6. 2. The application of claim 1, wherein the medicine is in oral or injectable dosage form, including powder, tablet, granule, capsule, oral liquid, emulsion or suspension.

7. The application of claim 1, wherein the medicine further comprises an auxiliary agent or a medicine for protecting kidneys and blood vessels.

8. 10. The application of claim 1, wherein the drug further comprises a pharmaceutically acceptable carrier, including a diluent, buffer, suspending agent, emulsion, granule, encapsulating agent, excipient, filler, adhesive, spray, transdermal agent, wetting agent, disintegrant, absorption enhancer, surfactant, colorant, flavoring agent, or adsorption carrier.

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