CN116919965A - Application of TRPM 1 specific small molecule inhibitor ML-SI3 - Google Patents
Application of TRPM 1 specific small molecule inhibitor ML-SI3 Download PDFInfo
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- CN116919965A CN116919965A CN202310593039.8A CN202310593039A CN116919965A CN 116919965 A CN116919965 A CN 116919965A CN 202310593039 A CN202310593039 A CN 202310593039A CN 116919965 A CN116919965 A CN 116919965A
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- kidney disease
- chronic kidney
- preventing
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- adenine
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- OVTXOMMQHRIKGL-UHFFFAOYSA-N n-[2-[4-(2-methoxyphenyl)piperazin-1-yl]cyclohexyl]benzenesulfonamide Chemical compound COC1=CC=CC=C1N1CCN(C2C(CCCC2)NS(=O)(=O)C=2C=CC=CC=2)CC1 OVTXOMMQHRIKGL-UHFFFAOYSA-N 0.000 title claims abstract description 42
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- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
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- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/03—Organic compounds
- A23L29/045—Organic compounds containing nitrogen as heteroatom
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Polymers & Plastics (AREA)
- Nutrition Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Food Science & Technology (AREA)
- Urology & Nephrology (AREA)
- Mycology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application discloses an application of a TRPM 1 specific small molecule inhibitor ML-SI3 in preparation of a product for preventing and treating anemia caused by chronic kidney disease. The beneficial effects of the application are as follows: the application provides a new medicine for treating anemia caused by chronic kidney disease, and has good market value and clinical application prospect.
Description
Technical Field
The application belongs to the technical field of biological medicines, and particularly relates to an application of a TRPM 1 specific small molecule inhibitor ML-SI3 in preparation of a medicine for preventing and treating anemia caused by chronic kidney disease.
Background
Anemia is a common complication of chronic kidney disease (chronic kidney disease; CKD), and it is counted that the prevalence of CKD in our country is about 10.8% of the adult population, with more than 50% of patients having anemia associated therewith. CKD causes anemia primarily due to kidney damage resulting in reduced production of Erythropoietin (EPO). EPO is a hormone produced primarily by the kidneys and stimulates myelogenous erythrocytes. Erythropoiesis Stimulating Agents (ESAs) supplemented with iron agents are the main means of clinical treatment of anemia caused by CKD, and currently commonly used ESAs preparations mainly include recombinant human erythropoietin (rHuEPO), alfa (darbeptin Alfa) and the like, which have similar effects and may cause adverse reactions such as hypertension, cardiovascular events, vascular abnormalities and the like. Luo Shasi he (Roxadurtat, code FG-4592) is a newly developed drug for treating anemia caused by CKD in recent years. The Proline Hydroxylase (PHDs) inhibitor (HIF-PHIs) can promote endogenous EPO production and increase erythrocyte and hemoglobin production, and has the advantages of oral administration, improving iron metabolism, directly promoting physiological EPO secretion and the like. However, due to its cardiovascular side effects, the us FDA cardiovascular and renal drug consultation committee (CRDAC) is against the use of roflumilast for the treatment of anemia due to CKD. Therefore, the research on a new effective drug for treating the anemia caused by the CKD without side effects has good market value.
Disclosure of Invention
The main purpose of the application is to provide an application of a TRPM 1 specific small molecule inhibitor ML-SI3 in preparation of medicines for preventing and treating anemia caused by chronic kidney disease, and the medicines provide a new medicine for treating anemia caused by chronic kidney disease, and have good market value and clinical application prospects.
In order to achieve the above object, the present application provides the following technical solutions:
in a first aspect, the application provides application of a TRPM 1 specific small molecule inhibitor ML-SI3 in preparation of a product for preventing and treating anemia caused by chronic kidney disease.
The TRPM 1 specific small molecule inhibitor ML-SI3 can improve the damage degree of kidney tissues.
The application mentioned above is used as a preferred embodiment, and the product for preventing and treating anemia caused by chronic kidney disease includes, but is not limited to, a medicament for preventing and treating anemia caused by chronic kidney disease, and a health functional food for preventing and treating anemia caused by chronic kidney disease.
In a second aspect of the present application, there is provided a medicament for preventing and treating anemia caused by chronic kidney disease, wherein the medicament comprises TRPML1 specific small molecule inhibitor ML-SI3 as a main active ingredient.
The medicine for preventing and treating anemia caused by chronic kidney disease, as a preferred embodiment, further comprises pharmaceutically acceptable carriers and/or auxiliary materials.
Preferably, the dosage forms of the medicament include, but are not limited to, tablets, granules, oral liquids, capsules, pills, and injections.
In a third aspect of the present application, a health functional food for preventing and treating anemia caused by chronic kidney disease is provided, wherein the health functional food uses TRPML1 specific small molecule inhibitor ML-SI3 as a main active ingredient.
The health-care functional food for preventing and treating anemia caused by chronic kidney disease is taken as a preferred embodiment and further comprises a carrier and/or auxiliary materials acceptable in food.
The beneficial effects of the application are as follows: the application provides a new medicine for treating anemia caused by chronic kidney disease, and has good market value and clinical application prospect.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application, are incorporated in and constitute a part of this specification. The drawings and their description are illustrative of the application and are not to be construed as unduly limiting the application. In the drawings:
FIG. 1 is a chemical structure diagram of a TRPM 1 specific small molecule inhibitor ML-SI3 of the present application;
FIG. 2 is a graph showing the preparation and administration time patterns of mice with an anemia model due to adenine-induced chronic kidney disease;
FIG. 3 is a graph showing the analysis of the body weight effects of ML-SI3 co-administration on mice with anemia due to adenine-induced chronic kidney disease;
FIG. 4A is a graph showing the analysis of blood urea nitrogen effects of ML-SI3 co-administration on mice with anemia due to adenine-induced chronic kidney disease;
FIG. 4B is a graph showing the analysis of the effects of ML-SI3 co-administration on the effects of creatinine in mice with anemia due to adenine-induced chronic kidney disease;
FIG. 5A is a graph showing the analysis of the effect of ML-SI3 co-administration on the erythrocyte count in mice with anemia due to adenine-induced chronic kidney disease;
FIG. 5B is a graph showing the analysis of the results of the effects of ML-SI3 co-administration on hemoglobin in mice with anemia due to adenine-induced chronic kidney disease;
FIG. 5C is a graph showing the analysis of the effect of ML-SI3 co-administration on the hematocrit of mice with anemia due to adenine-induced chronic kidney disease;
FIG. 6 is a graph showing the analysis of serum EPO effects of ML-SI3 co-administration on mice with anemia due to adenine-induced chronic kidney disease;
FIG. 7A is an optical microscopy image of kidney tissue damage in mice with anemia due to adenine-induced chronic kidney disease given in combination with ML-SI 3;
FIG. 7B is a graph showing the results of scoring by optical microscopy of renal tissue damage in mice with anemia due to adenine-induced chronic kidney disease in combination with ML-SI 3.
Detailed Description
In order that those skilled in the art will better understand the present application, a technical solution of embodiments of the present application will be clearly and completely described in the following description with reference to examples, and it is apparent that the described embodiments are only some embodiments of the present application, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the present application without making any inventive effort, shall fall within the scope of the present application.
It should be noted that, without conflict, the embodiments of the present application and features of the embodiments may be combined with each other. The application will be described in detail below with reference to the drawings in connection with embodiments.
The application discloses a novel application of TRPM 1 specific small molecule inhibitor ML-SI3, and application of the inhibitor in preparing a medicament for preventing and treating anemia caused by chronic kidney disease. In particular to the application of the inhibitor in preparing a medicament for preventing and treating anemia caused by chronic kidney disease, and the inhibitor can improve the damage of kidney tissues.
In the treatment of anemia caused by chronic kidney disease, the effective dose of the TRPM 1 specific small molecule inhibitor ML-SI3 is 3mg/kg.
The application also provides a medicine for preventing and treating anemia caused by chronic kidney disease, which takes a TRPML1 specific small molecule inhibitor ML-SI3 as a main active ingredient and can contain pharmaceutically acceptable carriers and/or auxiliary materials. The medicine can be tablet, granule, oral liquid, capsule, pill, injection and other dosage forms.
The application also provides a health-care functional food for preventing and treating anemia caused by chronic kidney disease, the health-care functional food takes a TRPML1 specific small molecule inhibitor ML-SI3 as a main active ingredient, and the food can comprise acceptable carriers and/or auxiliary materials on products.
Studies have shown that lysosomal cation channel TRPML1 is a target for regulating and controlling the release of cations in lysosomes, and that changing the activity of TRPML1 channels by using agonists or inhibitors of TRPML1 can regulate and control the release of cations (including ferrous ions) in lysosomes, while ferrous ions participate in the regulation and control of activity of Hypoxia Inducible Factors (HIF) by PHDs so as to control the transcription of EPO. Therefore, the following is a test for confirming that the specific small molecule inhibitor ML-SI3 of TRPM 1 (its chemical structure is shown in FIG. 1) has therapeutic effect on anemia caused by chronic kidney disease:
1. test method
First, an Adenine-induced anemia model was prepared using C57BL/6J mice, and divided into 4 groups, namely, a Control group (Control), an Adenine group (Adene), an Adenine-combined ML-SI3 group (Adene+ML-SI 3), and an Adenine-combined FG-4592 positive Control group (Adene+FG-4592). The modeling and ML-SI3, FG-4592 intervention methods are shown in FIG. 2:
adenine group: a molding module for molding anemia caused by adenine lavage induced chronic kidney disease;
Adenine+ML-SI3 group: to model anemia caused by adenine lavage induced chronic kidney disease and to intraperitoneally administer ML-SI 3.
Adenine+FG-4592 group: molding and intraperitoneally administering FG-4592 to an administration group for the treatment of anemia caused by adenine lavage induced chronic kidney disease;
fig. 2 specifically shows: the corresponding doses of ML-SI3 (3 mg/kg) and FG-4592 (10 mg/kg; medChemexpress, monmouth Junction, NJ, USA) were administered by intraperitoneal injection to the Adene+MLSI 3 group, adene+FG-4592 group, respectively, 2 and 1 days before the molding was started, and then to the control group, adene group, 0.9% saline (10 mL/kg) was administered by intraperitoneal injection. After 2 interventions, molding was started. The corresponding doses of Adenine (50 mg/kg; sigma-Aldrich, st.Louis, MO, USA) of the Adenine group, adenine+ML-SI3 group, adenine+FG-4592 group and distilled water (5 mL/kg) of the control group were given by intragastric administration on a body weight basis at the same time each day; the corresponding doses of ML-SI3 and FG-4592 were given by intraperitoneal injection into the Adenine+ML-SI3 group, adenine+FG-4592 group at the same time every other day. The body weight of the mice was recorded daily during the molding period and counted. For 28 days from the molding, the body weight of the mice was measured on the 28 th day, and after anesthesia with 1% sodium pentobarbital (40 mg/kg), whole blood, serum, and kidney tissues of the mice were collected for corresponding index detection and experimental operation.
2. ML-SI3 co-administration improves weight loss in mice with anemia due to adenine-induced chronic kidney disease
2.1 measurement method
The body weight of the mice was measured and recorded daily on days 1-28 of the model, the body weight ratio on the corresponding days was calculated using the body weight on day 1 as the base body weight, and the body weight change curve was made using Graphpad7.0 software.
The results are shown in FIG. 3: compared with adenine group, the combined administration of ML-SI3 can obviously improve the condition of weight loss of mice with anemia caused by adenine-induced chronic kidney disease, and the effect is not obviously different from FG-4592.
3. Combination administration of ML-SI3 improves kidney function index of mice with anemia caused by adenine-induced chronic kidney disease
3.1 measurement method
After the mice are anesthetized, the two side beards are sheared off by the ophthalmology, the heads of the mice are downwards pressed, the necks of the mice are lightly pressed to enable the eyeballs to protrude, the eyeballs are removed by the curved forceps to take venous blood, and the venous blood is dripped into a sterile centrifuge tube. After 30 minutes of standing at room temperature, the supernatant serum was transferred to another sterile centrifuge tube by centrifugation at 3000 rpm for 15 minutes at 4 ℃.
The serum Urea (Urea) and serum Creatinine (Creatinine) levels of mice were measured separately in accordance with the protocol using the serum Urea (S03036, shenzhen Lei Du) and serum Creatinine kit (DICT-500,BioAssay Systems,Hayward,CA,USA). The mice Blood Urea Nitrogen (BUN) level was then calculated as: BUN (mg/dL) =urea (mmol/L) 2.8. All data were counted and statistically mapped with Graphpad7.0 software.
The results are shown in FIG. 4: compared with adenine group, the combined administration of ML-SI3 can relieve the rise of blood urea nitrogen (figure 4A) and blood creatinine (figure 4B) of mice with anemia caused by adenine-induced chronic kidney disease, the two renal function indexes are obviously improved, and the effect is not obviously different from FG-4592.
4. Improvement of anemia index of adenine-induced chronic kidney disease-induced anemia mice by ML-SI3 combined administration
4.1 measurement method
After the mice were anesthetized, 110 μl of mouse venous whole blood was taken in the same manner as in 3.1 and was instilled into EDTA anticoagulation blood collection tubes (BD, broken Bow, NE, USA), turned upside down to allow the blood to be sufficiently combined with EDTA, and immediately placed at 4 ℃ for preservation. The room temperature was taken out and equilibrated for 15 minutes before the detection, the conventional detection of mouse blood was performed by a fully automatic blood cell analyzer (BC-2800 vet, shenzhen Mairui), the data of red blood cell count (RBC), hemoglobin (Hemoglobin) and Hematocrit (Hematocrit) were recorded, all the data were counted and a statistical graph was made by Graphpad7.0 software.
The results are shown in FIG. 5: compared with adenine group, the combined administration of ML-SI3 can relieve the reduction of erythrocyte count (figure 5A), hemoglobin (figure 5B) and hematocrit (figure 5C) of mice with anemia caused by adenine-induced chronic kidney disease, three anemia indexes are obviously improved, and the effect is not obviously different from FG-4592.
5. Combination ML-SI3 administration improves serum EPO level reduction in mice with anemia caused by adenine-induced chronic kidney disease
5.1 measurement method
After the mice were anesthetized, 60. Mu.L of the serum from the mice was taken in the same manner as in 3.1, and the serum EPO level was measured within three days after the blood collection by dropping into a sterile centrifuge tube and preserving at-80 ℃.
Mouse serum was removed prior to detection and thawed in an ice bath, and mouse serum EPO levels were detected according to the protocol using mouse serum EPO ELISA kit (MEP 00B, R & D Systems, minneapolis, MN, USA), all data were counted and statistically mapped with Graphpad7.0 software.
The results are shown in FIG. 6: compared with adenine group, the combined administration of ML-SI3 can relieve the reduction of serum EPO level (figure 6) of mice with anemia caused by adenine-induced chronic kidney disease, the serum EPO level is obviously increased, and the effect is not obviously different from FG-4592.
6. ML-SI3 combined administration obviously improves kidney tissue damage of mice with anemia caused by adenine-induced chronic kidney disease
6.1 test method
After anesthesia, the mice were perfused with PBS buffer by left ventricular puncture. Whole kidneys were collected, fixed in 4% paraformaldehyde for 24 hours at room temperature, embedded in paraffin, cut into 3 μm thick slices with a microtome, dewaxed in xylene for 30 minutes, removed, sequentially transferred to 100%, 95%, 90%, 80%, 70% ethanol solutions for 5 minutes each time, finally transferred to distilled water, and left for 5 minutes. The dewaxed sections were immersed in hematoxylin dye for 3 minutes, rinsed for 1 minute, transferred to 95% ethanol, and after 1 minute, stained in eosin dye for 1 minute. After the staining is completed, the sections are transferred to 70%, 80%, 90%, 95%, 100% ethanol solution for dehydration, then transferred to xylene for 5 minutes, and finally can be sealed and stored by a neutral glue sealing sheet. The pathologist was asked to observe under an optical microscope (fig. 7A) and score according to the scoring method described in table 1. All data were counted and statistically mapped with Graphpad7.0 software (fig. 7B).
TABLE 1 marking criteria for pathological tissue of anemia caused by adenine-induced chronic kidney disease
The results are shown in FIG. 7: compared with adenine group, the combined administration of ML-SI3 can reduce the kidney tissue injury level of mice with anemia caused by adenine-induced chronic kidney disease, which suggests that ML-SI3 has a significant improvement effect on kidney injury of anemia caused by chronic kidney disease, and the effect is not significantly different from FG-4592.
In conclusion, compared with adenine mice, we found that mice in the group administered with ML-SI3 had significantly improved body weight loss, renal function index, anemia index, serum EPO level, and kidney injury, and the effect was not significantly different from FG-4592.
The experimental results prove that: the ML-SI3 micromolecule compound can obviously improve the anemia of mice with anemia model caused by adenine-induced chronic kidney disease. The application provides a new medicine for treating anemia caused by chronic kidney disease, and has good market value and clinical application prospect.
The foregoing is merely a preferred embodiment of the present application, and it should be noted that modifications and additions may be made to those skilled in the art without departing from the method of the present application, which modifications and additions are also to be considered as within the scope of the present application.
Claims (7)
1. An application of TRPML1 specific small molecule inhibitor ML-SI3 in preparing product for preventing and treating anemia caused by chronic kidney disease is provided.
2. The use according to claim 1, wherein the product for preventing and treating anemia caused by chronic kidney disease includes, but is not limited to, a medicament for preventing and treating anemia caused by chronic kidney disease, a health functional food for preventing and treating anemia caused by chronic kidney disease.
3. A medicine for preventing and treating anemia caused by chronic kidney disease is characterized in that the medicine takes a TRPML1 specific small molecule inhibitor ML-SI3 as a main active ingredient.
4. A medicament for the prevention and treatment of anemia arising from chronic kidney disease according to claim 3, further comprising pharmaceutically acceptable carriers and/or excipients.
5. A medicament for the prevention and treatment of anemia due to chronic kidney disease according to claim 3, wherein the dosage form of the medicament includes, but is not limited to, tablets, granules, oral liquids, capsules, pills, injections.
6. A health-care functional food for preventing and treating anemia caused by chronic kidney disease is characterized in that the health-care functional food takes a TRPML1 specific small molecule inhibitor ML-SI3 as a main active ingredient.
7. The functional health food for preventing and treating anemia due to chronic kidney disease according to claim 6, further comprising a food acceptable carrier and/or adjuvant.
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| WO2021067946A1 (en) * | 2019-10-04 | 2021-04-08 | Goldfinch Bio, Inc. | Biomarker-based treatment of focal segmental glomerulosclerosis and diabetic kidney disease |
| CN113197900A (en) * | 2021-01-27 | 2021-08-03 | 徐州医科大学 | Application of TRPML1 specific small molecule inhibitor ML-SI3 |
| CN114028384A (en) * | 2021-02-24 | 2022-02-11 | 中国医学科学院皮肤病医院(中国医学科学院皮肤病研究所) | Application of licorice isoflavane derivative in preparation of medicine for preventing, relieving or/and treating pruritus |
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| WO2021067946A1 (en) * | 2019-10-04 | 2021-04-08 | Goldfinch Bio, Inc. | Biomarker-based treatment of focal segmental glomerulosclerosis and diabetic kidney disease |
| CN113197900A (en) * | 2021-01-27 | 2021-08-03 | 徐州医科大学 | Application of TRPML1 specific small molecule inhibitor ML-SI3 |
| CN114028384A (en) * | 2021-02-24 | 2022-02-11 | 中国医学科学院皮肤病医院(中国医学科学院皮肤病研究所) | Application of licorice isoflavane derivative in preparation of medicine for preventing, relieving or/and treating pruritus |
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