CN116919965B - 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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- CN116919965B CN116919965B CN202310593039.8A CN202310593039A CN116919965B CN 116919965 B CN116919965 B CN 116919965B CN 202310593039 A CN202310593039 A CN 202310593039A CN 116919965 B CN116919965 B CN 116919965B
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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
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- 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
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- 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
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- 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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- General Health & Medical Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Food Science & Technology (AREA)
- Urology & Nephrology (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of a TRPM 1 specific small molecule inhibitor ML-SI3 in preparing a medicine for preventing and treating anemia caused by chronic kidney disease. The beneficial effects of the invention are as follows: the invention 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 invention 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 D I SEASE; 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. The main cause of anemia in CKD is reduced production of erythropoietin (erythropoiet i n; EPO) due to kidney damage. 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), albendamustine (Darbepoet i n Al fa) 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 (Roxadustat, code FG-4592) is a newly developed drug for treating anemia caused by CKD in recent years. The Proline Hydroxylase (PHDs) inhibitor (H I F-PH I s) can promote endogenous EPO production and increase erythrocyte and hemoglobin production, and has the advantages of being orally taken, 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 invention provides the following technical solutions:
In a first aspect, the invention 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 above-mentioned application, as a preferred embodiment, 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.
In a second aspect of the present invention, 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.
The beneficial effects of the invention are as follows: the invention 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 invention;
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 invention 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.
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 (Adenine), an adenine-combined ML-SI3 group (Adenine +ML-SI 3), and an adenine-combined FG-4592 positive Control group (Adenine +FG-4592). The modeling and ML-SI3, FG-4592 intervention methods are shown in FIG. 2:
Adenine groups: 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 Adenine +ML-SI3 group, adenine +FG-4592 group, respectively, 2 days and 1 day before the start of molding, and then to the control group, adenine group, 0.9% saline (10 mL/kg) by intraperitoneal injection. After 2 interventions, molding was started. The corresponding doses of adenine (50 mg/kg; sigma-Aldrich, st.Louis, MO, USA) were given to Adenine, adenine +ML-SI3, adenine +FG-4592 groups by intragastric administration and distilled water (5 mL/kg) to the control group by intragastric administration at the same time of day; the corresponding doses of ML-SI3 and FG-4592 were given by intraperitoneal injection into 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 Graphpad 7.0 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 Graphpad 7.0 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 Michael), 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 Graphpad 7.0 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 Graphpad 7.0 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 Graphpad 7.0 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 invention 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 invention, 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 invention, which modifications and additions are also to be considered as within the scope of the present invention.
Claims (1)
1. Application of TRPML1 specific small molecule inhibitor ML-SI3 in preparing medicine for preventing and treating anemia caused by chronic kidney disease is provided.
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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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