CN111110667A - Application of carboxylic acid in preparation of GLUT9 and URAT1 double-target inhibitor - Google Patents
Application of carboxylic acid in preparation of GLUT9 and URAT1 double-target inhibitor Download PDFInfo
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- CN111110667A CN111110667A CN201911372671.XA CN201911372671A CN111110667A CN 111110667 A CN111110667 A CN 111110667A CN 201911372671 A CN201911372671 A CN 201911372671A CN 111110667 A CN111110667 A CN 111110667A
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- Prior art keywords
- acid
- carboxylic acid
- glut9
- urat1
- uric acid
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Physical Education & Sports Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of carboxylic acid in preparing GLUT9 and URAT1 dual-target inhibitors. The inventor finds that acetic acid, propionic acid or butyric acid has an inhibiting effect on URAT1 and GLUT9 which are important drug targets for treating hyperuricemia, and the transporters are also abundantly present in the intestinal tract. The content of acetic acid, propionic acid or butyric acid in the body is increased by giving a patient with hyperuricemia a sufficient amount of acetic acid, propionic acid or butyric acid, or by adjusting the diet, so that the excretion of uric acid from the kidney and the intestinal tract is expected to be promoted, and the method has important significance for improving or treating the hyperuricemia.
Description
Technical Field
The invention relates to a novel application of a compound, in particular to an application of carboxylic acid in preparing GLUT9 and URAT1 dual-target inhibitors.
Background
Hyperuricemia is a metabolic disease with a high incidence rate after hyperlipidemia and hyperglycemia, the incidence rate of Chinese adults is up to 12 percent, particularly the incidence rate of Chinese adults is up to 20 percent in coastal towns, and the main reasons are caused by poor dietary habits, such as eating a large amount of seafood, drinking excessive, taking excessive large fish meat and the like. The content of purine in food is too high, uric acid is the final metabolite of purine substances in vivo, and adenine, hypoxanthine and the like in vivo are catalyzed by xanthine oxidase in liver to generate uric acid purine, and the uric acid purine is excessively ingested or metabolic abnormality can cause hyperuricemia, so that gout, hypertension, cardiovascular diseases, kidney diseases and the like are caused.
The current clinical choices of uric acid-lowering drugs are few, and xanthine oxidase inhibitors are the current clinical commonly used uric acid-lowering drugs which act on the liver to inhibit the generation of uric acid, such as allopurinol, febuxostat and the like. However, allopurinol is liable to cause hypersensitive reaction, and febuxostat is also proposed by the FDA to be liable to induce cardiovascular and cerebrovascular diseases. Except for the liver, the kidney is the main site of blood uric acid excretion, the excretion of the kidney urate depends on the balance of reabsorption and excretion of urate, the transport process relates to a series of transporters, including uric acid reabsorption transporter, namely urate anion transporter 1(SLC22A12, URAT1), glucose transporter 9(SLC2A9, GLUT9) and OAT1, OAT3 and the like for promoting uric acid excretion, the drugs are uric acid excretion promoting drugs, which can promote the excretion of uric acid from urine by inhibiting URAT1 on renal tubules, such as Benzbromarone (BM), Probenecid (PB), Lesinurad and the like, but the clinical application of the drugs is limited due to large side effect, poor drug effect and the like. Although URAT1 has been the hot target for finding uric acid lowering drugs, GLUT9 has attracted more attention in maintaining uric acid levels in normal blood. GLUT9 is a urate transporter with high capacity and low affinity. Research shows that GLUT9 may play a more important role than URAT1, but no uric acid lowering drug targeting GLUT9 is found at present.
The intestinal tract is also an important organ for uric acid excretion, and about 30% of uric acid in human bodies is excreted from the intestinal tract. An increasing number of studies suggest that intestinal urate excretion disorder is an important pathogenesis of primary hyperuricemia. Various transporters exist in the intestinal tract, such as URAT1, GLUT9, ABCG2 and the like, but at present, no research related to the uric acid transport in the intestinal tract exists, and how the intestinal tract can play a role in reducing uric acid is further researched.
Disclosure of Invention
The invention aims to provide application of a compound in preparing a GLUT9 and URAT1 dual-target inhibitor.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
use of a compound selected from the group consisting of:
a C2-C4 carboxylic acid or a pharmaceutically acceptable derivative thereof.
In some examples, the derivatives may be metabolized in vivo, further in the digestive tract, particularly in the intestinal tract, to produce carboxylic acids of C2-C4.
In some examples, the derivative is a salt or ester of a carboxylic acid of C2 to C4.
In some examples, the carboxylic acid of C2 to C4 is selected from acetic acid, propionic acid, or butyric acid.
In a second aspect of the present invention, there is provided:
use of a compound selected from the group consisting of:
a C2-C4 carboxylic acid or a pharmaceutically acceptable derivative thereof.
In some examples, the derivatives may be metabolized in vivo, further in the digestive tract, particularly in the intestinal tract, to produce carboxylic acids of C2-C4.
In some examples, the derivative is a salt or ester of a carboxylic acid of C2 to C4.
In some examples, the carboxylic acid of C2 to C4 is selected from acetic acid, propionic acid, or butyric acid.
In some examples, the composition is an oral formulation or an enterally administrable formulation.
In some examples, the oral formulation is selected from the group consisting of a capsule, a tablet, a granule, an effervescent tablet, an oral liquid.
In some examples, the oral formulation is an enteric agent.
In a third aspect of the present invention, there is provided:
use of a compound for the preparation of a composition for treating or ameliorating hyperuricemia, said compound being selected from the group consisting of:
a C2-C4 carboxylic acid or a pharmaceutically acceptable derivative thereof.
In some examples, the derivatives may be metabolized in vivo, further in the digestive tract, particularly in the intestinal tract, to produce carboxylic acids of C2-C4.
In some examples, the derivative is a salt or ester of a carboxylic acid of C2 to C4.
In some examples, the carboxylic acid of C2 to C4 is selected from acetic acid, propionic acid, or butyric acid.
In some examples, the composition is an oral formulation or an enterally administrable formulation.
In some examples, the oral formulation is selected from the group consisting of a capsule, a tablet, a granule, an effervescent tablet, an oral liquid.
In some examples, the oral formulation is an enteric agent.
In a fourth aspect of the present invention, there is provided:
the application of the composition in preparing preparations for reducing uric acid and treating or improving hyperuricemia, wherein the composition has acceptable C2-C4 producing carboxylic acid bacteria and/or fermentation substrates thereof.
In some examples, the carboxylic acid of C2 to C4 is selected from acetic acid, propionic acid, or butyric acid.
In some examples, the carboxylic acid bacteria producing C2-C4 are located in the intestinal tract.
In some examples, the fermentation substrate contains dietary fiber.
The invention has the beneficial effects that:
the inventor finds that acetic acid, propionic acid or butyric acid has an inhibiting effect on URAT1 and GLUT9 which are important drug targets for treating hyperuricemia, and the transporters are also abundantly present in the intestinal tract. The content of acetic acid, propionic acid or butyric acid in the body is increased by giving a patient with hyperuricemia a sufficient amount of acetic acid, propionic acid or butyric acid, or by adjusting the diet, so that the excretion of uric acid from the kidney and the intestinal tract is expected to be promoted, and the method has important significance for improving or treating the hyperuricemia.
Drawings
FIG. 1 is a dose-response curve of the inhibition of GLUT9 by acetic acid, propionic acid, butyric acid at different concentrations and IC50The value is obtained.
FIG. 2 is a dose-response curve of the inhibitory effect of acetic acid, propionic acid and butyric acid on GLUT9 at different concentrations and the half Inhibitory Concentration (IC)50)。
Detailed Description
The technical scheme of the invention is further explained by combining experiments.
The inventor utilizes the electrogenesis characteristic of GLUT9 in uric acid transfer, namely the characteristic that the potential of a cell membrane changes, and researches the inhibition effect of butyric acid on GLUT9 by using a patch clamp technology; by passing14[C]Isotopic uric acid uptake experiments were performed to study the inhibitory effect of butyric acid on URAT 1.
The specific experimental protocol is as follows:
1) cloning the fragment containing the activity of encoding GLUT9 or URAT1 onto an expression vector to construct a recombinant plasmid;
2) transfecting the recombinant plasmid into a mammalian cell;
3) performing patch-clamp electrophysiological experiments on transfected cells or14[C]Uric acid uptake assay using an extracellular fluid containing uric acid or a solution containing uric acid14[C]Uric acid uptake buffer;
4) adding butyric acid to the uric acid-containing extracellular fluid, and judging that butyric acid is a compound having an inhibitory effect on GLUT9 when the recorded current produced by the cells is significantly reduced compared with that produced without adding butyric acid (only adding uric acid solution); butyric acid pre-incubation of URAT1 transfected HEK293T cells for 15min before adding butyric acid and butyric acid14[C]Uric acid, which is judged to be a compound having an inhibitory effect on URAT1 when the radioactive CPM value is significantly decreased as compared to the case where butyric acid is not added (only uric acid solution is added).
The patch clamp electrophysiological experiment specifically comprises the following steps: firstly, co-transfecting GLUT9 recombinant plasmid pcDNA3.1(-) -GLUT9 and fluorescent gene fragment EGFP to HEK293T cells with 70-80% of fusion degree, digesting the cells and re-inoculating the cells 18-24h after transfectionThe poly-lysine-containing gel is planted on a pre-treated cover glass sheet, and can be used for recording whole-cell patch clamp after cells are attached to the wall. The invention respectively measures the current change generated by the fact that uric acid external liquid (the concentration of uric acid is 1mM) containing butyric acid with different concentrations stimulates HEK293T cells expressing GLUT9, and obtains the half Inhibitory Concentration (IC) of butyric acid inhibiting GLUT9 through nonlinear fitting calculation50Value). The specific operation steps of the electrophysiological experiment are as follows: placing a glass slide in extracellular fluid connected with a metal electrode, moving a glass microelectrode above a cell with fluorescence, applying negative pressure, forming a high-resistance seal larger than 1G omega between the electrode and the cell, clamping the cell at-30 mV after capacitance compensation, perfusing the external fluid containing butyric acid and uric acid at the speed of 2-3ml/min, recording the change of the current generated by the cell when only perfusing the uric acid and perfusing the butyric acid and the uric acid simultaneously, and calculating the inhibition rate of the butyric acid on GLUT 9. Wherein the inhibition rate calculation formula is as follows: I/I 0100% (wherein I is the current during simultaneous perfusion of butyric acid-containing uric acid external liquid, I0Current when only uric acid external liquid was perfused).
14[C]The uric acid uptake experiment comprises the following specific steps: firstly, transfecting a URAT1 recombinant plasmid pcDNA3.1(+) -URAT1 to HEK293T cells with 70-80% of fusion degree, digesting the cells 18-24h after transfection, and re-inoculating the cells on a 96-well plate pretreated by polylysine to prepare the cell for uric acid uptake experiments after the cells are attached to the wall. The present invention measures butyric acid (5mM,4mM, 2mM, 1mM,0.5mM) in different concentrations14[C]Uric acid uptake buffer solution (14[C]Uric acid concentration of 50 μ M) was incubated with HEK293T cells expressing URAT 1. The half Inhibitory Concentration (IC) of butyric acid inhibiting URAT1 was calculated by nonlinear fitting50Value). The specific operation of the uric acid uptake experiment is as follows: firstly, washing cells for 3 times by using buffer solution without uric acid, discarding liquid in holes, adding buffer solution containing butyric acid for pre-incubation for 15min, and then discarding liquid in the holes. Followed by addition of a mixture containing butyric acid and14[C]cells were incubated for 15min in uric acid uptake buffer. After the ingestion is finished, 0.1M NaOH is added into each hole to crack cells for 30min, liquid scintillation liquid is added, and the liquid scintillation liquid is transferred into a liquid scintillation instrument to record the change of butyric acid on the radiation value CPM valueAnd calculating the rate of inhibition of URAT1 by butyric acid. Wherein the inhibition rate calculation formula is as follows: CPM/CPM 0100% (wherein CPM is the radioactivity value when butyric acid-containing uric acid uptake buffer was added simultaneously, CPM0Radioactivity value when only uric acid external liquid was added).
Reagents and methods:
preparation of kanamycin and ampicillin: dissolve 1g kanamycin in sufficient ddH2And O, finally, diluting to 20mL, filtering, sterilizing, subpackaging into small parts, storing at-20 ℃, and diluting 1000 times when in use.
Preparing competent cells: the whole gold Trans1-T1 is competent (cat # CD501-02), and is used for transformation of target genes after dissolving on ice before use.
Preparation of liquid E.coli culture medium: 5g of peptone, 5g of sodium chloride and 2.5g of yeast extract are weighed into a 500mL clean bottle respectively, 500mL of ultrapure water is added and uniformly stirred, and the mixture is sterilized at the high temperature of 121 ℃ for 20 min. After sterilization, the temperature was reduced to 37 ℃ and 500. mu.L of kanamycin (100. mu.L/100 mL) was added and shaken well, and stored at 4 ℃ for further use.
Preparation of solid Escherichia coli culture medium: 3g of peptone, 3g of sodium chloride, 1.5g of yeast extract and 4.5g of agar were weighed into 500mL of a clean bottle, 300mL of ultrapure water was added thereto, and the mixture was sterilized at 121 ℃ for 20 min. After completion of sterilization, the solid medium was left at room temperature, and 300. mu.L of kanamycin (100. mu.L/100 mL) was added to the unset medium, shaken, poured into a sterile petri dish, and stored at 4 ℃ after coagulation for use.
In vitro inhibition of GLUT9 by acetic acid, propionic acid, or butyric acid
1) Construction of pcDNA3.1(-) -GLUT9 recombinant plasmid
The invention selects pcDNA3.1(-) as expression vector; the active fragment of the target Gene sequence is GLUT9 full length (Gene ID: 117591). Under the action of T4 ligase, the target gene fragment is cloned to pcDNA3.1(-) vector, the plasmid is transformed into Escherichia coli and cultured for 16h at 37 ℃, then the single clone is picked up and placed in the prepared liquid culture solution for culturing, and the bacteria are shaken for 16 h. After shaking the bacteria, extracting the plasmid, selecting a sample and sending the sample to sequencing for final confirmation.
2) Co-transfection of cells
When the HEK293T cells were grown to 90%, the HEK293T cells were seeded into 24-well plates and placed at 37 ℃ with 5% CO2After the cells are cultured in an incubator for 18-24h, the transient transfection of the DNA-liposome complex is carried out when the cell fusion rate is about 70-80%.
The specific transfection steps are as follows: to two 1.5mL EP tubes (tube No. 1 and tube No. 2), 25 μ L of Opti medium was added, and then to tube No. 1, 600ng of two plasmids (mgut 9: EGFP ═ 2: 1): 250ng and 1 uL of P3000TMMixing uniformly; 0.75 mu L P3000 was added to tube No. 2TMSwirling the sample tube for 10 seconds, and standing for 5 min; mixing the two tubes, vortexing for 10 s, standing for 20min, dripping into 500 μ L/hole of new culture medium, standing at 37 deg.C with 5% CO2Culturing in an incubator for 18-24 h.
Wherein, Opti culture medium: the opti-MEM fraction contains HEPES, 2400mg/L sodium bicarbonate, hypoxanthine, thymidine, sodium pyruvate, L-glutamine, trace elements, growth factors, and trace phenol red.
3) Preparation of cell slide
And observing the expression of green fluorescent protein EGFP 18-24h after transfection, digesting transfected cells, re-inoculating the cells onto a circular cover glass with the radius of 12mm pretreated by polylysine, and after 5h, adhering the cells to the wall, thus being used for recording the whole-cell patch clamp.
4) Whole cell patch clamp recordings
(1) Preparation of intracellular and extracellular fluids
The external liquid formula comprises: 140mM/L NaCl, 5mM/L KCl, 1mM/L MgCl2、2mM/L CaCl210mM/LHEPES and 10mM/L D-glucose, the pH thereof was adjusted to about 7.4 with 0.1M NaOH, and the mixture was filtered through a 0.22 μ M microporous membrane and stored at 4 ℃ for further use.
The formula of the internal liquid is as follows: 140mM/100mL KCl, 1mM/100mL MgCl25mM/100mL EGTA, 10mM/100mLHEPES, KOH adjusted pH to about 7.4, using 0.22 μm microporous membrane filtration, and left at 4 ℃ for storage.
(2) Preparing external liquid containing medicine and uric acid at the same time: dissolving 8.4mg of uric acid powder by using 0.1M NaOH to obtain 25mM uric acid mother liquor; 800. mu.L of uric acid mother liquor was added to 19.2mL of the external solution, and the mixture was mixed well to obtain 20mL of 1mM of uric acid external solution. It should be used immediately. The external liquid containing the medicine and the uric acid, namely the medicine solution and the uric acid solution are mixed uniformly to obtain the final set concentration.
(3) Preparing an electrode: a borosilicate capillary glass tube is used, after two-step drawing by a drawing instrument, the diameter of a tip is about 1-5 mu m, internal liquid (about one third to one half of an electrode) is added into the tail of a micro-electrode by a syringe in a flushing mode, and air bubbles are removed slightly.
(4) The electrode is arranged on the electrode arm of the patch clamp, positive pressure is slightly applied, and liquid connection potential compensation is performed after the electrode is moved into the liquid level. Moving the glass microelectrode above the selected cell under a microscope, the resistance increases by approximately 0.2-0.4 M.OMEGA.upon contact with the cell, the positive pressure is removed and a negative pressure is applied.
(5) When a high-resistance seal larger than 1G omega is formed between the electrode and the HEK293T cell membrane, fast capacitance compensation and slow capacitance compensation are carried out. Then the cells were clamped at-30 mV and a short and powerful negative pressure was applied to rupture the membranes.
(6) After the cells were stabilized, the whole cell mode recorded the current. And carefully adding a sample prepared by using an extracellular fluid right above the cells by adopting a perfusion system, and recording the change condition of the current. The experiment was repeated 3 times.
(7) And (3) changing different perfusion solutions, respectively recording the current change of the cells before and after adding the uric acid external liquid or adding the uric acid external liquid containing the medicine, and drawing a current curve by using Clampfit and AI processing.
(8) If the instantaneous maximum current generated by GLUT9 is obviously reduced at 0.15s, carboxylic acid is a uric acid-reducing small molecular compound with an inhibiting effect on GLUT 9.
As a result: FIG. 1 is a dose-response curve of the inhibition of GLUT9 by acetic acid, propionic acid and butyric acid at different concentrations and IC thereof50The value is obtained.
As shown in FIG. 1, acetic acid, propionic acid, butyric acid inhibited GLUT9 in a concentration-dependent manner, its IC50The values are 2.07, 1.20 and 1.19mM, respectively, indicating thatAcids, propionic acid, butyric acid are inhibitors of GLUT 9.
In vitro inhibition of URAT1 by acetic acid, propionic acid or butyric acid
Construction of pcDNA3.1(+) -EGFP-URAT1 recombinant plasmid
The invention selects pcDNA3.1(+) as expression vector; the active fragment of the target Gene sequence is the full length of URAT1 (Gene ID: 116085). Under the action of T4 link enzyme, the target gene fragment is cloned to pcDNA3.1(+) -EGFP vector, the plasmid is transformed into escherichia coli and cultured for 16h at 37 ℃, then the single clone is picked up and placed in prepared liquid culture solution for culturing, and the bacteria are shaken for 16 h. After shaking the bacteria, extracting the plasmid, selecting a sample and sending the sample to sequencing for final confirmation.
2) Polylysine coated 96-well plate
Poly-lysine PDL (0.1mg/ml) was plated on 96-well plates for 24h, and then PDL was discarded and oven-dried for 12h for use.
3) Cell transfection
When HEK293T cells grew to 90%, HEK293T cells were seeded into PDL-coated 96-well plates at 37 ℃ with 5% CO2After the cells are cultured in an incubator for 18-24h, the transient transfection of the DNA-liposome complex is carried out when the cell fusion rate is about 70-80%.
The specific transfection steps are as follows: two 1.5mL EP tubes (tubes 1 and 2) were filled with 25. mu.L of Opti medium, respectively, and then tube 1 was filled with 500ng of the above plasmid and 1. mu.L of P3000TMMixing uniformly; add 0.75. mu.L of Lipo 3000 to tube No. 2TMSwirling the sample tube for 10 seconds, and standing for 5 min; mixing the two tubes, vortexing for 10 s, standing for 20min, dripping into 500 μ L/hole (10 μ L/hole) of new culture medium, standing at 37 deg.C and containing 5% CO2Culturing in an incubator for 18-24 h.
Wherein, Opti culture medium: the opti-MEM ingredient contains HEPES, 2400mg/L sodium bicarbonate, hypoxanthine, thymidine, sodium pyruvate, L-glutamine, trace elements, growth factors, and trace phenol red.
4)14[C]Uric acid uptake assay
(1) Preparation of uptake buffer
The formula is as follows: 140mM NaCl, 5mM KCl, 1mM MgCl2、2mM CaCl210mM HEPES and 10mM D-glucose, the pH of the mixture was adjusted to about 7.4 with 0.1M NaOH, and the mixture was filtered through a 0.22 μ M microporous membrane and stored at 4 ℃ for further use.
(2) Preparing a drug-containing uptake buffer: the used carboxylic acid mother liquor is 1 g/ml; when in use, the extract is diluted by an intake buffer solution to obtain the required concentration, and is preferably prepared for use.
(3) Preparation of the composition contains14[C]Uptake solution of uric acid and carboxylic acid: prepared with uptake buffer at a concentration of 100. mu.M14[C]Mixing uric acid solution with carboxylic acid solution dissolved in intake buffer solution with different concentrations in equal volume to obtain final concentration of 50 μ M14[C]Uric acid and carboxylic acid with different concentrations are mixed for ingestion.
(4)14[C]The uric acid uptake experiment comprises the following specific steps: the medium in HEK293T cells transfected with URAT1 was discarded and the cells were washed 3 times with 200. mu.L of uptake buffer. Adding 100 μ L of uptake buffer containing carboxylic acid (5,4,2,1,0.5mM) with different concentrations for pre-incubation for 15min, adding uptake buffer containing both medicine and uric acid after pre-incubation is finished, incubating for 15min, immediately discarding the liquid in the well, adding ice-cold DPBS buffer to wash the cells for 3 times, 200 μ L each time. Finally, 40 μ L of 0.1M NaOH is added to lyse cells for 30min, 0.2mL of liquid scintillation fluid is added, the liquid scintillation fluid is transferred to a liquid scintillation instrument to record the influence of whether carboxylic acid is added or not on the change of the radiation value CPM value, and the half Inhibition Concentration (IC) of the carboxylic acid for inhibiting URAT1 is calculated through nonlinear fitting50Value). Wherein the inhibition rate calculation formula is as follows: CPM/CPM 0100% (wherein CPM is the radioactivity associated with the addition of a carboxylic acid-containing uric acid uptake buffer, CPM0Radioactivity value when only uric acid external liquid was added).
As a result: FIG. 2 is a dose-response curve of the inhibitory effect of acetic acid, propionic acid and butyric acid at different concentrations on URAT1 and IC thereof50The value is obtained.
As shown in FIG. 2, acetic acid, propionic acid, butyric acid all inhibited URAT1 in a concentration-dependent manner, the IC of which50The values are 1.02, 2.06 and 2.37mM, which shows that acetic acid, propionic acid and butyric acid are inhibitors of URAT1And (4) preparing the preparation.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. Use of a compound selected from the group consisting of:
a C2-C4 carboxylic acid or a pharmaceutically acceptable derivative thereof.
2. Use of a compound selected from the group consisting of:
a C2-C4 carboxylic acid or a pharmaceutically acceptable derivative thereof.
3. Use of a compound for the preparation of a composition for treating or ameliorating hyperuricemia, said compound being selected from the group consisting of:
a C2-C4 carboxylic acid or a pharmaceutically acceptable derivative thereof.
4. Use according to claims 1 to 3, characterized in that: the derivatives can be metabolized in vivo to produce carboxylic acids of C2-C4.
5. Use according to claim 4, characterized in that: the derivative is salt or ester of carboxylic acid of C2-C4.
6. Use according to claims 1 to 3, characterized in that: the carboxylic acid of C2-C4 is selected from acetic acid, propionic acid or butyric acid.
7. Use according to claim 2 or 3, characterized in that: the composition is an oral preparation or an intestinal administration preparation.
8. Use according to claim 6, characterized in that: the oral preparation is selected from capsules, tablets, granules, effervescent tablets and oral liquid.
9. The application of a composition in preparing a preparation for reducing uric acid and treating or improving hyperuricemia, wherein the composition has acceptable C2-C4 producing carboxylic acid bacteria and/or fermentation substrates thereof, and preferably, the C2-C4 carboxylic acid is selected from acetic acid, propionic acid or butyric acid.
10. Use according to claim 9, characterized in that: the fermentation substrate contains dietary fiber.
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| CN110487877A (en) * | 2019-07-11 | 2019-11-22 | 南方医科大学 | A method of screening anti-trioxypurine small molecule compound |
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